Aaisha Kabli

BASIC EMBRYOLOGY

TOPIC 1 - PRIMORDIAL GERM CELLS. MITOSIS AND MEIOSIS. DEVELOPMENT OF GONADS.

PRIMORDIAL GERM CELLS

• Primordial germ cells (PGCs) that are formed in the epiblast during the second week, move through the
primi ve streak during gastrula on, and migrate to the wall of the yolk sac
• During the fourth week, these cells begin to migrate from the yolk sac toward the developing gonads,
where they arrive by the end of the h week.
• In prepara on for fer liza on, germ cells undergo gametogenesis (to form gametes), which includes
meiosis, to reduce the number of chromosomes and cytodi eren a on to complete their matura on.
MITOSIS
• Mitosis is the process whereby one cell divides, giving rise to two daughter cells that are gene cally
iden cal to the parent cell
• Before a cell enters mitosis, each chromosome replicates its DNA.
o During this replica on phase, chromosomes are extremely long, they are spread di usely
through the nucleus, and they cannot be recognized with the light microscope.
• Prophase:
o the chromosomes begin to coil, contract, and condense.
o Each chromosome now consists of two parallel subunits, chroma ds, that are joined at a narrow
region common to both called the centromere.
o throughout prophase, the chromosomes con nue to condense, shorten, and thicken, but only
at prometaphase do the chroma ds become dis nguishable
• Metaphase:
o the chromosomes line up in the equatorial plane,
o Each is a ached by microtubules extending from the centromere to the centriole, forming the
mito c spindle
• Anaphase:
o the centromere of each chromosome divides
o followed by migra on of chroma ds to opposite poles of the spindle
• Telophase:
o chromosomes uncoil and lengthen
o the nuclear envelope reforms
o cytoplasm divides
• Each daughter cell receives half of all doubled chromosome material and thus maintains the same
number of chromosomes as the mother cell.
MEIOSIS
• Meiosis is the cell division that takes place in the germ cells to generate male and female gametes
• Meiosis requires two cell divisions, meiosis I and meiosis II, to reduce the number of chromosomes to
the haploid number of 23
• Meiosis I
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 o male and female germ cells (spermatocytes and primary oocytes) replicate their DNA so that
each of the 46 chromosomes is duplicated into sister chroma ds.
o homologous chromosomes then align themselves in pairs, a process called synapsis.
o Homologous pairs then separate into two daughter cells, thereby reducing the chromosome
number from diploid to haploid.
• Meiosis II
o sister chroma ds separate.
o Each gamete then contains 23 chromosomes.
• Each germ cell contains a haploid number of chromosomes so that at fer liza on, the diploid number
of 46 is restored.
• Crossover:
o the interchange of chroma d segments between paired homologous chromosomes
o As separa on occurs, points of interchange are temporarily united and form an X-like structure,
a chiasma
o The approximately 30 to 40 crossovers (one or two per chromo- some) with each meio c I
division are most frequent between genes that are far apart on a chromosome.
• Gene c variability is enhanced through:
o Crossover, which redistributes gene c material
o Random distribu on of homologous chromosomes to the daughter cells
• Polar bodies:
o Females:
▪ one primary oocyte gives rise to four daughter cells, each with 22 plus 1 X chromosomes
▪ Only one of these develops into a mature gamete (mature oocyte)
▪ The other 3, the polar bodies, receive litlle cytoplasm and degenerate during subsequent
development.
o Males:
▪ one primary spermatocyte gives rise to four daughter cells, two with 22 plus 1 X
chromosomes and two with 22 plus 1 Y chromosomes
▪ All four develop into mature gametes.
• Basically:
o Primordial germ cell ! a er M1 ! a er M2 (gamete)
o Primary spermatocyte ! secondary spermatocytes ! sperma ds (! spermatozoa)
o Oogonia ! (Primary oocyte) ! secondary oocyte (+a polar body) ! mature oocyte (+3 polar
bodies)
DEVLEOPMENT OF THE INDIFFERENT GONAD
• Although the sex of the embryo is determined gene cally at the me of fer liza on, the gonads do not
acquire male or female morphological characteris cs un l the seventh week of development.
• Gonads appear ini ally as a pair of longitudinal ridges, the genital or gonadal ridges.
• They are formed by prolifera on of the epithelium and a condensa on of underlying mesenchyme.
• Primordial germ cells originate in the epiblast, migrate through the primi ve streak, and by the third
week, reside among endoderm cells in the wall of the yolk sac close to the allantois
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 • During the fourth week, they migrate by ameboid movement along the dorsal mesentery of the
hindgut, arriving at the primi ve gonads at the beginning of the h week and invading the genital
ridges in the sixth week.
• If they fail to reach the ridges, the gonads do not develop. Hence, the primordial germ cells have an
induc ve in uence on development of the gonad into ovary or tes s.
• Shortly before and during arrival of primordial germ cells, the epithelium of the genital ridge
proliferates, and epithelial cells penetrate the underlying mesenchyme.
• Here they form a number of irregularly shaped cords, the primi ve sex cords.
• In both male and female embryos, these cords are connected to surface epithelium, and it is impossible
to di eren ate between the male and female gonad.
TESTIS
• If the embryo is gene cally male, the primordial germ cells carry an XY sex chromosome complex.
Under in uence of the SRY gene on the Y chromosome, which encodes the tes s-determining factor,
the primi ve sex cords con nue to proliferate and penetrate deep into the medulla to form the tes s or
medullary cords
• Toward the hilum of the gland, the cords break up into a network of ny cell strands that later give rise
to tubules of the rete tes s.
• During further development, a dense layer of brous connec ve ssue, the tunica albuginea, separates
the tes s cords from the surface epithelium
• In the fourth month, the tes s cords become horseshoe-shaped, and their extremi es are con nuous
with those of the rete tes s.
• Tes s cords are now composed of primi ve germ cells and sustentacular cells of Sertoli derived from
the surface epithelium of the gland.
• Inters al cells of Leydig, derived from the original mesenchyme of the gonadal ridge, lie between the
tes s cords.
• By the eighth week, Leydig cells begin produc on of testosterone and the tes s is able to in uence
sexual di eren a on of the genital ducts and external genitalia.
• Tes s cords remain solid un l puberty, when they acquire a lumen, thus forming the seminiferous
tubules.
• Once the seminiferous tubules are canalized, they join the rete tes s tubules, which in turn enter the
ductuli e erentes.
• These e erent ductules are the remaining parts of the excretory tubules of the mesonephric system.
• They link the rete tes s and the mesonephric or Wol ian duct, which becomes the ductus deferens
OVARY
• In female embryos with no Y chromosome, primi ve sex cords dissociate into irregular cell clusters.
These clusters, containing groups of primi ve germ cells, occupy the medullary part of the ovary. Later,
they disappear and are replaced by a vascular stroma that forms the ovarian medulla
• The surface epithelium of the female gonad, unlike that of the male, con nues to proliferate. In the
seventh week, it gives rise to a second genera on of cords, cor cal cords, which penetrate the
underlying mesenchyme but remain close to the surface
• In the third month, these cords split into isolated cell clusters. Cells in these clusters con nue to
proliferate and begin to surround each oogonium with a layer of epithelial cells called follicular cells.
• SUMMARY:
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 o XX sex chromosome con gura on, medullary cords of the gonad regress, and a secondary
genera on of cor cal cords develops. In embryos with an XY sex chromosome complex,
medullary cords develop into tes s cords, and secondary cor cal cords fail to develop
TOPIC 2. MATURATION OF GAMETES: OOGENESIS.
• Oogenesis is the process whereby oogonia di eren ate into mature oocytes.
• Events before birth:
o Once PGCs have arrived in the gonad of a gene c female, they di eren ate into oogonia (by
mitosis)
o These cells undergo a number of mito c divisions
o By the end of the third month, they are arranged in clusters, surrounded by a layer of at
epithelial cells, called follicular cells (derived from the surface epithelium covering the ovary).
o The majority of oogonia con nue to divide by mitosis, but some of them arrest their cell division
in prophase of meiosis I (diplotene stage) and form primary oocytes
o This arrested state is produced by oocyte matura on inhibitor (OMI), a small pep de secreted
by follicular cells.
o A primary oocyte, together with its surrounding at epithelial cells (follicular cells), is known as
a primordial follicle
o by the h month of prenatal development, the total number of germ cells in the ovary reaches
its maximum, es mated at 7 million.
o At this me, cell death begins, and many oogonia as well as primary oocytes degenerate and
become atre c.
o By the seventh month, the majority of oogonia have degenerated except for a few near the
surface.
o At birth, there are no oogonia
o The total number of primary oocytes at birth is es mated to vary from 600,000 to 800,000.
• Events at puberty:
o Primary/ preantral follicle :
▪ As primordial follicles begin to grow, surrounding follicular cells change from at to
cuboidal and proliferate to produce a stra ed epithelium of granulosa cells, and the
unit is called a primary follicle
▪ Granulosa cells rest on a basement membrane separa ng them from surrounding
ovarian connec ve ssue (stromal cells) that form the theca folliculi.
▪ Also, granulosa cells and the oocyte secrete a layer of glycoproteins on the surface of the
oocyte, forming the zona pellucida
o Secondary follicle:
▪ As follicles con nue to grow, cells of the theca folliculi organize into an inner layer of
secretory cells, the theca interna, and an outer brous capsule, the theca externa.
▪ Also, small, ngerlike processes of the follicular cells extend across the zona pellucida
and interdigitate with microvilli of the plasma membrane of the oocyte. These processes
are important for transport of materials from follicular cells to the oocyte.
o Vesicular/ antral follicle:
▪ As development con nues, uid- lled spaces appear between granulosa cells.
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 ▪ Coalescence of these spaces forms the antrum, and the follicle is termed a vesicular or
an antral follicle.
▪ Ini ally, the antrum is crescent-shaped, but with me, it enlarges
o Mature vesicular/ gra an follicle:
▪ The antrum has enlarged considerably, is lled with follicular uid
▪ Granulosa cells surrounding the oocyte remain intact and form the cumulus oophorus.
▪ At maturity, the mature vesicular (graa an) follicle may be 25 mm or more in diameter.
▪ It is surrounded by the theca interna, which is composed of cells having characteris cs of
steroid secre on, rich in blood vessels, and the theca externa, which gradually merges
with the ovarian connec ve ssue
o With each ovarian cycle, a number of follicles begin to develop, but usually, only one reaches
full maturity. The others degenerate and become atre c.
o Fate of the oocyte within the follicle:
▪ When the secondary follicle is mature, a surge in luteinizing hormone (LH) induces the
preovulatory growth phase.
▪ Meiosis I is completed, resul ng in forma on of two daughter cells of unequal size, each
with 23 double-structured chromosomes
▪ One cell, the secondary oocyte, receives most of the cytoplasm; the other, the rst polar
body, receives prac cally none.
▪ The rst polar body lies between the zona pellucida and the cell membrane of the
secondary oocyte in the perivitelline space
▪ The cell then enters meiosis II but arrests in metaphase approximately 3 hours before
ovula on.
o If the oocyte is fer lized ! Meiosis II is completed
o If not ! the cell degenerates approximately 24 hours a er ovula on
TOPIC 3. MATURATION OF GAMETES: SPERMATOGENESIS AND SPERMIOGENESIS.
MIGRATION OF PGCs AND ITS ROLE IN THE DEVELOPMENT OF GONADS
• Spermatogenesis, which begins at puberty, includes all of the events by which spermatogonia are
transformed into spermatozoa.
• At birth, germ cells in the male infant can be recognized in the sex cords of the tes s as large, pale cells
surrounded by suppor ng cells, which are derived from the surface epithelium of the tes s and are
called sustentacular cells or Sertoli cells.
• Shortly before puberty, the sex cords acquire a lumen and become the seminiferous tubules.
• At about the same me, PGCs give rise to spermatogonial stem cells.
• At regular intervals, cells emerge from this stem cell popula on to form type A spermatogonia, and
their produc on marks the ini a on of spermatogenesis.
• Type A cells undergo a limited number of mito c divisions. The last cell division produces type B
spermatogonia, which then divide to form primary spermatocytes.
• Primary spermatocytes then enter a prolonged prophase (22 days) followed by rapid comple on of
meiosis I and forma on of secondary spermatocytes.
• During the second meio c division, these cells immediately begin to form haploid sperma ds.
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 • Throughout this series of events, from the type A cells to the sperma ds, cytokinesis is incomplete so
that successive cell genera ons are joined by cytoplasmic bridges.
• Thus, the progeny of a single type A spermatogonium form a clone of germ cells that maintain contact
throughout di eren a on, un l individual sperm are separated from residual bodies.
• Furthermore, spermatogonia and sperma ds remain embedded in the cytoplasmic processes of Sertoli
cells throughout their development.
• In this manner, Sertoli cells:
o support and protect the germ cells
o par cipate in their nutri on
o assist in the release of mature spermatozoa.
• Spermatogenesis is regulated by LH produc on by the pituitary gland.
• LH binds to receptors on Leydig cells (in the inters um) and s mulates testosterone produc on, which
in turn binds to Sertoli cells to promote spermatogenesis.
• Follicle-s mula ng hormone (FSH) is also essen al because its binding to Sertoli cells s mulates
tes cular uid produc on and synthesis of intracellular androgen receptor proteins.
• Spermiogenesis- The series of changes resul ng in the trans- forma on of sperma ds into
spermatozoa.
• These changes include
o forma on of the acrosome, which covers half of the nuclear surface and contains enzymes to
assist in penetra on of the egg and its surrounding layers during fer liza on
o condensa on of the nucleus;
o forma on of neck, middle piece, and tail
o shedding of most of the cytoplasm as residual bodies that are phagocy zed by Sertoli cells.
• In humans, spermiogenesis takes approximately 74 days, and approximately 300 million sperm cells are
produced daily.
• When fully formed, spermatozoa enter the lumen of seminiferous tubules. From there, they are pushed
toward the epididymis by contrac le elements in the wall of the seminiferous tubules. Although ini ally
only slightly mo le, spermatozoa obtain full mo lity in the epididymis.
• Gonads – Topic 1
TOPIC 4 – CELLULAR AND HORMONAL BACKROUND OF MENSTRUAL CYCLE
• At puberty, the female begins to undergo regular monthly cycles.
• These sexual cycles are controlled by the hypothalamus.
• Gonadotropin-releasing hormone (GnRH), produced by the hypothalamus, acts on cells of the anterior
lobe (adenohypophysis) of the pituitary gland, which in turn secrete gonadotropins. These hormones,
follicle-s mula ng hormone (FSH) and luteinizing hormone (LH), s mulate and control cyclic changes in
the ovary.
• At the beginning of each ovarian cycle, 15 to 20 primary-stage (preantral) follicles are s mulated to
grow under the in uence of FSH.
o (The hormone is not necessary to promote development of primordial follicles to the primary
follicle stage, but without it, these primary follicles die and become atre c.)
o Thus, FSH rescues 15 to 20 of these cells from a pool of con nuously forming primary follicles.
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 • Under normal condi ons, only one of these follicles reaches full maturity, and only one oocyte is
discharged; the others degenerate and become atre c.
• When a follicle becomes atre c, the oocyte and surrounding follicular cells degenerate and are replaced
by connec ve ssue, forming a corpus atre cum.
• FSH also s mulates matura on of follicular (granulosa) cells surrounding the oocyte.
• In turn, prolifera on of these cells is mediated by growth di eren a on factor 9, a member of the
transforming growth factor-B (TGF-B) family.
• In coopera on, theca interna and granulosa cells produce estrogens:
o Theca interna cells produce androstenedione and testosterone,
o and granulosa cells convert these hormones to estrone and 17 B-estradiol.
• As a result of this estrogen produc on:
o The uterine endometrium enters the follicular or prolifera ve phase.
o Thinning of the cervical mucus occurs to allow passage of sperm.
o The anterior lobe of the pituitary gland is s mulated to secrete LH.
• At midcycle, there is an LH surge that:
o Elevates concentra ons of matura on- promo ng factor, causing oocytes to complete meiosis I
and ini ate meiosis II
o S mulates produc on of progesterone by follicular stromal cells (luteiniza on)
o Causes follicular rupture and ovula on
• In the days immediately preceding ovula on, under the in uence of FSH and LH, the vesicular follicle
grows rapidly to a diameter of 25 mm to become a mature vesicular (graa an) follicle.
TOPIC 5- FERTILLIZATION
• Fer liza on is the process by which male and female gametes fuse
• It occurs in the ampullary region of the uterine tube.
o This is the widest part of the tube and is close to the ovary
• Spermatozoa may remain viable in the female reproduc ve tract for several days.
• Only 1% of sperm deposited in the vagina enter the cervix, where they may survive for many hours.
• Movement of sperm from the cervix to the uterine tube occurs by muscular contrac ons of the uterus
and uterine tube and very li le by their own propulsion.
• The trip from cervix to oviduct can occur as rapidly as 30 minutes or as slow as 6 days.
• A er reaching the isthmus, sperm become less mo le and cease their migra on.
• At ovula on, sperm again become mo le, perhaps because of chemoa ractants produced by cumulus
cells surrounding the egg
• Spermatozoa are not able to fer lize the oocyte immediately upon arrival in the female genital tract but
must rst undergo (1) capacita on and (2) the acrosome reac on
• Capacita on:
o Capacita on is a period of condi oning in the female reproduc ve tract that in the human lasts
approximately 7 hours.
o (Thus, speeding to the ampulla is not an advantage because capacita on has not yet occurred
and such sperm are not capable of fer lizing the egg.)
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 o Much of this condi oning occurs in the uterine tube and involves epithelial interac ons
between the sperm and the mucosal surface of the tube.
o During this me, a glycoprotein coat and seminal plasma proteins are removed from the plasma
membrane that overlies the acrosome.
o Only capacitated sperm can pass through the corona cells and undergo the acrosome reac on.
• The acrosome reac on:
o It occurs a er binding to the zona pellucida.
o It is induced by zona proteins.
o This reac on culminates in the release of enzymes needed to penetrate the zona pellucida,
including acrosin- and trypsin-like substances
• The phases of fer liza on include the following:
• Phase 1: Penetra on of the Corona Radiata
o Of the 200 to 300 million spermatozoa normally deposited in the female genital tract, only 300
to 500 reach the site of fer liza on.
o Only one of these fer lizes the egg.
o It is thought that the others aid the fer lizing sperm in penetra ng the barriers protec ng the
female gamete.
o Capacitated sperm pass freely through corona cells.
• Phase 2: Penetra on of the Zona Pellucida
o ZP3, a zona protein, mediates:
▪ binding
▪ acrosome reac on
o Release of acrosomal enzymes (acrosin) allows sperm to penetrate the zona, thereby coming in
contact with the plasma membrane of the oocyte.
o the plasma membrane is lined by cor cal granules that release lysosomal enzymes
o these enzymes alter proper es of the zona pellucida (zona reac on) to:
▪ prevent sperm penetra on (permeability of the zona pellucida changes)
▪ inac vate species-speci c receptor sites for spermatozoa on the zona surface.
o These reac ons prevent polyspermy (penetra on of more than one spermatozoon into the
oocyte).
o The oocyte membrane becomes impenetrable to other spermatozoa. Other spermatozoa have
been found embedded in the zona pellucida, but only one seems to be able to penetrate the
oocyte
• Phase 3: Fusion of the Oocyte and Sperm Cell Membranes
o Adhesion
▪ mediated by the interac on of integrins on the oocyte and their ligands, disintegrins, on
sperm.
o Fusion of membranes
▪ Because the plasma membrane covering the acrosomal head cap disappears during the
acrosome reac on, actual fusion is accomplished between the oocyte membrane and
the membrane that covers the posterior region of the sperm head.
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 ▪ Both the head and the tail of the spermatozoon enter the cytoplasm of the oocyte, but
the plasma membrane is le behind on the oocyte surface.
• As soon as the spermatozoon has entered the oocyte, the egg responds in three ways:
o 1. Cor cal and zona reac ons. (men oned before)
o 2. Resump on of the second meio c division.
▪ The oocyte nishes its second meio c division immediately a er entry of the
spermatozoon.
▪ One of the daughter cells, which receives hardly any cytoplasm, is known as the second
polar body; the other daughter cell is the de ni ve oocyte.
▪ Its chromosomes (22 plus X) arrange themselves in a vesicular nucleus known as the
female pronucleus
o 3. Metabolic ac va on of the egg.
▪ The ac va ng factor is probably carried by the spermatozoon.
▪ Ac va on encompasses the ini al cellular and molecular events associated with early
embryogenesis.
• The spermatozoon, meanwhile, moves forward un l it lies close to the female pronucleus.
• Its nucleus becomes swollen and forms the male pronucleus
• The tail detaches and degenerates.
• Morphologically, the male and female pronuclei are indis nguishable, and eventually, they come into
close contact and lose their nuclear envelopes.
• During growth of male and female pronuclei (both haploid), each pronucleus must replicate its DNA.
• Immediately a er DNA synthesis, chromosomes organize on the spindle in prepara on for a normal
mito c division.
• The 23 maternal and 23 paternal (double) chromosomes split longitudinally at the centromere, and
sister chroma ds move to opposite poles, providing each cell of the zygote with the normal diploid
number of chromosomes and DNA.
• As sister chroma ds move to opposite poles, a deep furrow appears on the surface of the cell, gradually
dividing the cytoplasm into two parts
• The main results of fer liza on are as follows:
o Restora on of the diploid number of chromosomes
▪ half from the father and half from the mother. Hence, the zygote contains a new
combina on of chromosomes di erent from both parents.
o Determina on of the sex of the new individual.
▪ An X-carrying sperm produces a female (XX) embryo, and a Y—carrying sperm produces
a male (XY) embryo.
o Ini a on of cleavage.
▪ Without fer liza on, the oocyte usually degenerates 24 hours a er ovula on.
TOPIC 6- SEGMENTATION. FORMATION OF BLASTOCYST. IMPLANTATION. MAJOR
CHARACTERISTICS OF EMBRYONIC AND ADULT STEM CELLS.
CLEAVAGE
• Once the zygote has reached the two-cell stage, it undergoes a series of mito c divisions, increasing the
numbers of cells.
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 • These cells, which become smaller with each cleavage division, are known as blastomeres.
• Un l the eight-cell stage, they form a loosely arranged clump. A er this, however, blastomeres
maximize their contact with each other, forming a compact ball of cells held together by ght junc ons
• This process, compac on, segregates inner cells, which communicate extensively by gap junc ons,
from outer cells.
• Approximately 3 days a er fer liza on, cells of the compacted embryo divide again to form a 16-cell
morula.
• Inner cells of the morula cons tute the inner cell mass, and surrounding cells compose the outer cell
mass.
o The inner cell mass gives rise to ssues of the embryo proper
o The outer cell mass forms the trophoblast, which later contributes to the placenta.
BLASTOCYST FORMATION AND IMPLANTATION
• About the me the morula enters the uterine cavity, uid begins to penetrate through the zona
pellucida into the intercellular spaces of the inner cell mass.
• Gradually, the intercellular spaces become con uent, and nally, a single cavity, the blastocele, forms.
At this me, the embryo is a blastocyst.
• Cells of the inner cell mass, now called the embryoblast, are at one pole, and those of the outer cell
mass, or trophoblast, a en and form the epithelial wall of the blastocyst.
• The zona pellucida has disappeared, allowing implanta on to begin.
• Trophoblas c cells over the embryoblast pole begin to penetrate between the epithelial cells of the
uterine mucosa on about the sixth day.
o L-selec n on trophoblast cells and its carbohydrate receptors on the uterine epithelium mediate
ini al a achment of the blastocyst to the uterus.
o Following capture by selec ns, further a achment and invasion by the trophoblast involve
integrins, expressed by the trophoblast and the extracellular matrix molecules laminin and
bronec n.
• Hence, by the end of the rst week of development, the human zygote has passed through the morula
and blastocyst stages and has begun implanta on in the uterine mucosa.
ESTABLISHMENT OF DORSAL-VENTRAL POLARITY AND CRANIAL-CAUDAL EMBRYONIC AXIS
• Under the in uence of broblast growth factors (FGFs) at the early blastocyst stage, cells in the
embryoblast di eren ate into epiblast and hypoblast cells.
o Ini ally, these cells are sca ered in the embryoblast, but near the me of implanta on, they
segregate to become a layer of epiblast cells dorsally and hypoblast cells ventrally, adjacent to
the blastocyst cavity (blastocele)
o Thus, a dorsal ventral polarity is established in the embryo.
• Some of the hypoblast cells are speci ed to form the anterior visceral endoderm (AVE), and these cells
migrate to what will become the cranial end of the embryo
o AVE cells are responsible for secre ng nodal antagonists, including cerberus and le y1, that act
on adjacent epiblast cells to specify the cranial end of the embryo.
o In the absence of these inhibitors, nodal establishes the primi ve streak at the caudal end of the
embryo.
o In this manner, the cranial-caudal embryonic axis is established.
WALL OF UTERUS
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 • At the me of implanta on, the mucosa of the uterus is in the secretory/progesta onal phase, during
which me uterine glands and arteries become coiled and the ssue becomes succulent.
• As a result, three dis nct layers can be recognized in the endometrium:
o a super cial compact layer
o an intermediate spongy layer
o and a thin basal layer
• Normally, the human blastocyst implants in the endometrium along the anterior or posterior wall of the
body of the uterus, where it becomes embedded between the openings of the glands

Fer liza on 12 to 24 hours a er ovula on

Two-cell stage 30 hours
Advanced morula stage reaching the uterine lumen 4 days
Early blastocyst stage 4.5 days
Early phase of implanta on 6 days
SUMMARY OF THE TIME SCALE

EMBRYONIC STEM CELLS

• Embryonic stem cells are derived from the inner cell mass of the embryo.
• Because these cells are pluripotent and can form virtually any cell or ssue type, they have the
poten al for curing a variety of diseases, including diabetes, Alzheimer and Parkinson diseases,
anemias, spinal cord injuries, and many others.
• Reproduc ve cloning-
o ES cells may be obtained from embryos a er IVF, a process called reproduc ve cloning.
o This approach has the disadvantage that the cells may cause immune rejec on because they
would not be gene cally iden cal to their hosts.
o The cells could be modi ed to circumvent this problem, however. Another issue with this
approach is based on ethical considera ons, as the cells are derived from viable embryos.
• Therapeu c cloning or soma c nuclear transfer-
o This technique has been devised to take nuclei from adult cells [e.g., skin] and introduce them
into enucleated oocytes.
o Oocytes are s mulated to di eren ate into blastocysts, and ES cells are harvested.
o Because the cells are derived from the host, they are compa ble gene cally, and because
fer liza on is not involved, the technique is less controversial.
ADULT STEM CELLS
• Adult ssues contain stem cells that may also prove valuable in trea ng diseases.
• These cells are restricted in their ability to form di erent cell types and, therefore, are mul potent, not
pluripotent, although scien sts are nding methods to circumvent this disadvantage.
• Adult stem cells isolated from rat brains have been used to cure Parkinson disease in rats, sugges ng
that the approach has promise.
• Disadvantages of the approach include:
o the slow rates of cell division characteris c of these cells
o and their scarcity, which makes them di cult to isolate in su cient numbers for experiments.
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 TOPIC 7- BODY CAVITIES IN THE EARLY STAGE OF EMRYONIC DEVELOPMENT: CAVITY
OF THE BLASTOCYST, AMNIOTIC CAVITY, CHORIONIC CAVITY, PRIMITIVE AND
SECUNDER YOLK SAC.
DAY 8 (just for info)
• The blastocyst is par ally embedded in the endometrial stroma.
• In the area over the embryoblast, the trophoblast has di eren ated into two layers:
o (1) an inner layer of mononucleated cells, the cytotrophoblast
o (2) an outer mul nucleated zone without dis nct cell boundaries, the syncy otrophoblast
• Mito c gures are found in the cytotrophoblast but not in the syncy otrophoblast.
• Thus, cells in the cytotrophoblast divide and migrate into the syncy otrophoblast, where they fuse and
lose their individual cell membranes.
• Cells of the inner cell mass or embryoblast also di eren ate into two layers:
o (1) a layer of small cuboidal cells adjacent to the blastocyst cavity, known as the hypoblast
o (2) a layer of high columnar cells adjacent to the amnio c cavity, the epiblast layer
• Together, the layers form a at disc. At the same me, a small cavity appears within the epiblast. This
cavity enlarges to become the amnio c cavity.
• Epiblast cells adjacent to the cytotrophoblast are called amnioblasts; together with the rest of the
epiblast, they line the amnio c cavity
DAY 9
• The blastocyst is more deeply embedded in the endometrium, and the penetra on defect in the
surface epithelium is closed by a brin coagulum
• At the embryonic pole:
o Vacuoles appear in the syncy um. When these vacuoles fuse, they form large lacunae
o This phase of trophoblast development is thus known as the lacunar stage
• At the abembryonic pole:
o Fla ened cells probably origina ng from the hypoblast form a thin membrane, the exocoelomic
(Heuser) membrane that lines the inner surface of the cytotrophoblast
o This membrane, together with the hypoblast, forms the lining of the exocoelomic cavity, or
primi ve yolk sac.
DAYS 11 AND 12
• The blastocyst is completely embedded in the endometrial stroma, and the surface epithelium almost
en rely covers the original defect in the uterine wall
• Establishment the uteroplacental circula on:
o The trophoblast is characterized by lacunar spaces in the syncy um that form an
intercommunica ng network.
o This network is par cularly evident at the embryonic pole; (at the abembryonic pole, the
trophoblast s ll consists mainly of cytotrophoblas c cells)
o Cells of the syncy otrophoblast penetrate deeper into the stroma and erode the endothelial
lining of the maternal capillaries.
o These capillaries, which are congested and dilated, are known as sinusoids.
o The syncy al lacunae become con nuous with the sinusoids, and maternal blood enters the
lacunar system and begins to ow through the trophoblas c system
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 • Forma on of extraembryonic mesoderm:
o In the mean me, a new popula on of cells appears between the inner surface of the
cytotrophoblast and the outer surface of the exocoelomic cavity.
o These cells, derived from yolk sac cells, form a ne, loose connec ve ssue, the extraembryonic
mesoderm, which eventually lls all of the space between the trophoblast externally and the
amnion and exocoelomic membrane internally
• Forma on of extraembryonic cavity:
o Soon, large cavi es develop in the extraembryonic mesoderm, and when these become
con uent, they form a new space known as the extraembryonic cavity, or chorionic cavity
o This space surrounds the primi ve yolk sac and amnio c cavity, except where the germ disc is
connected to the trophoblast by the connec ng stalk.
• The extraembryonic mesoderm lining the cytotrophoblast and amnion is called the extraembryonic
soma c mesoderm; the lining covering the yolk sac is known as the extraembryonic splanchnic
mesoderm
• Growth of the bilaminar disc is rela vely slow compared with that of the trophoblast; consequently, the
disc remains very small (0.1 to 0.2 mm).
• Decidua reac on of the endometrium:
o Cells of the endometrium become polyhedral and loaded with glycogen and lipids
o Intercellular spaces are lled with extravasate, and the ssue is edematous.
o These changes, at rst, are con ned to the area immediately surrounding the implanta on site
but soon occur throughout the endometrium.
DAY 13
• The surface defect in the endometrium has usually healed.
• Occasionally, however, bleeding occurs at the implanta on site as a result of increased blood ow into
the lacunar spaces.
• Forma on of primary villi:
o Cells of the cytotrophoblast proliferate locally and penetrate into the syncy otrophoblast,
forming cellular columns surrounded by syncy um.
o Cellular columns with the syncy al covering are known as primary villi
• Forma on of secondary/ de ni ve yolk sac:
o In the mean me, the hypoblast produces addi onal cells that migrate along the inside of the
exocoelomic membrane.
o These cells proliferate and gradually form a new cavity within the exocoelomic cavity, known as
the secondary yolk sac or de ni ve yolk sac.
o This yolk sac is much smaller than the original exocoelomic cavity, or primi ve yolk sac.
o During its forma on, large por ons of the exocoelomic cavity are pinched o . These por ons
are represented by exocoelomic cysts, which are o en found in the extraembryonic coelom or
chorionic cavity
• Forma on of chorionic cavity:
o Meanwhile, the extraembryonic coelom expands and forms a large cavity, the chorionic cavity.
o The extraembryonic mesoderm lining the inside of the cytotrophoblast is then known as the
chorionic plate.
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 o The only place where extraembryonic mesoderm traverses the chorionic cavity is in the
connec ng stalk.
▪ With development of blood vessels, the stalk becomes the umbilical cord.
TOPIC 8 – FORMATION AND EARLY DIFFERENTIATION OF EMBRYOBLASTS AND
TROPHOBLASTS. TERATOGENICITY.
• Forma on and early di eren a on of embryoblasts and trophoblasts – Topic 7
• Teratogenicity - a manifesta on of developmental toxicity, by the induc on or the increase of the
frequency of structural disorders in the progeny.
• Teratogen - A factor that causes a birth defect, such as a drug or environmental toxicant.
• Agents that cause birth defects include:
o Viruses – Eg: rubella, Zika
o Radia on
o Drugs – Eg: an -convulsants, and an depressants
o Social drugs – Eg: cigare es, marijuana, and alcohol
o Hormones
o Maternal diabetes.
• E ects of teratogens depend on:
o the maternal and fetal genotype,
o the stage of development when exposure occurs,
o the dose and dura on of exposure of the agent.
• Many major malforma ons are produced during the ‘period of embryogenesis’ or ‘teratogenic period’
which is from the third to eighth weeks.
• Many techniques are available to assess the growth and developmental status of the fetus:
o Ultrasound
o Noninvasive prenatal screening (NIPS) technique:
▪ Maternal serum screening
o Invasive procedures:
▪ Amniocentesis, (needle is placed into the amnio c cavity and a uid sample is
withdrawn)
▪ Chorionic villus sampling (CVS), (aspira ng a ssue sample directly from the placenta)
▪ Percutaneous umbilical blood sampling [PUBS], (a needle is used to draw blood from the
umbilical cord in utero.)
• Example: Anencephaly, hydrocephaly, cle lip and palate are caused by the teratogen Aminopterin
TOPIC 9 - FORMATION AND DERIVATIVES OF EXTRAEMBRYONIC MESODERM. EARLY
STEPS OF PLACENTATION.
• Forma on of extra embryonic mesoderm- Topic 7
• Deriva ves of extraembryonic mesoderm
o The fetal component of the placenta is derived from the trophoblast and extraembryonic
mesoderm
FURTHER DEVELOPMENT OF TROPHOBLAST
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• By the beginning of the third week, the trophoblast is characterized by primary villi that consist of a
cytotrophoblas c core covered by a syncy al layer
• During further development, mesodermal cells (from extraembryonic mesoderm) penetrate the core of
primary villi and grow toward the decidua. The newly formed structure is known as a secondary villus
• By the end of the third week, mesodermal cells in the core of the villus begin to di eren ate into blood
cells and small blood vessels, forming the villous capillary system. The villus is now known as a ter ary
villus or a de ni ve placental villus.
• Capillaries in ter ary villi make contact with capillaries developing in the mesoderm of the chorionic
plate and in the connec ng stalk.
• These vessels, in turn, establish contact with the intraembryonic circulatory system, connec ng the
placenta and the embryo.
• Hence, when the heart begins to beat in the fourth week of development, the villous system is ready to
supply the embryo with proper essen al nutrients and oxygen.
• Meanwhile, cytotrophoblas c cells in the villi penetrate progressively into the overlying syncy um un l
they reach the maternal endometrium.
• Here, they establish contact with similar extensions of neighboring villous stems, forming a thin outer
cytotrophoblast shell
• This shell gradually surrounds the trophoblast en rely and a aches the chorionic sac rmly to the
maternal endometrial ssue.
• Villi that extend from the chorionic plate to the decidua basalis (decidual plate: the part of the
endometrium where the placenta will form) are called stem or anchoring villi.
• Those that branch from the sides of stem villi are free (terminal) villi, through which exchange of
nutrients and other factors will occur.
PLACENTATION
• It is the forma on or arrangement of the placenta.
• The placenta is the organ that facilitates nutrient and gas exchange between the maternal and fetal
compartments.
• The fetal component of the placenta is derived from the trophoblast and extraembryonic mesoderm
(the chorionic plate); the maternal component is derived from the uterine endometrium.
• Maternal blood is delivered to the placenta by spiral arteries in the uterus.
• Endovascular invasion- Erosion of these maternal vessels by cytotrophoblast cells, to release blood into
intervillous spaces
o Cytotrophoblast cells, released from the ends of anchoring villi invade the terminal ends of
spiral arteries, where they replace maternal endothelial cells, crea ng hybrid vessels containing
both fetal and maternal cells.
o Cytotrophoblast cells undergo an epithelial-to-endothelial transi on.
o Invasion transforms maternal vessels from small-diameter, high-resistance vessels to larger
diameter, low-resistance vessels, that can provide increased quan es of maternal blood to
intervillous spaces
• Exchange between the 2 circula ons through villi:
o But by the beginning of the fourth month, cytotrophoblas c cells and some connec ve ssue
cells, in the free villi, disappear.
o The syncy um and endothelial wall of the blood vessels are then the only layers that separate
the maternal and fetal circula ons.
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 o Frequently, the syncy um becomes very thin, and large pieces containing several nuclei may
break o and drop into the intervillous blood lakes.
o These pieces, known as syncy al knots, enter the maternal circula on and usually degenerate
without causing any symptoms.
o Disappearance of cytotrophoblas c cells progresses from the smaller to larger villi, and although
some always persist in large villi, they do not par cipate in the exchange between the two
circula ons.
CHORION FRONDOSUM AND DECIDUA BASALIS
• NOTE: decidua is the func onal layer of the endometrium, which is shed during parturi on.
• Villi on the embryonic pole con nue to grow and expand, giving rise to the chorion frondosum (bushy
chorion).
• The decidua over the chorion frondosum, the decidua basalis, consists of a compact layer of large cells,
decidual cells, with abundant amounts of lipids and glycogen. This layer, the decidual plate, is ghtly
connected to the chorion.
• Villi on the abembryonic pole degenerate, and by the third month, this side of the chorion, now known
as the chorion laeve, is smooth
• The decidual layer over the abembryonic pole is the decidua capsularis. With growth of the chorionic
vesicle, this layer becomes stretched and degenerates.
• Subsequently, the chorion laeve comes into contact with the uterine wall (decidua parietalis) on the
opposite side of the uterus, and the two fuse, oblitera ng the uterine lumen.
• Hence, the only por on of the chorion par cipa ng in the exchange process is the chorion frondosum,
which, together with the decidua basalis, makes up the placenta.
• Similarly, fusion of the amnion and chorion to form the amniochorionic membrane obliterates the
chorionic cavity. It is this membrane that ruptures during labor (breaking of the water).
STRUCTURE OF THE PLACENTA
• By the beginning of the fourth month, the placenta has two components:
o (1) a fetal por on, formed by the chorion frondosum, and
o (2) a maternal por on, formed by the decidua basalis.
• In the junc onal zone, trophoblast and decidual cells intermingle.
• This zone, characterized by decidual and syncy al giant cells, is rich in amorphous extracellular
material.
• By this me, most cytotrophoblast cells have degenerated.
• Between the chorionic and decidual plates are the intervillous spaces, which are lled with maternal
blood. They are derived from lacunae in the syncy otrophoblast and are lined with syncy um of fetal
origin.
• During the fourth and h months, the decidua forms a number of decidual septa, which project into
intervillous spaces but do not reach the chorionic plate.
• These septa have a core of maternal ssue, but their surface is covered by a layer of syncy al cells
• As a result of this septum forma on, the placenta is divided into a number of compartments, or
cotyledons
• Because the decidual septa do not reach the chorionic plate, contact between intervillous spaces in the
various cotyledons is maintained.
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 • As a result of the con nuous growth of the fetus and expansion of the uterus, the placenta also
enlarges.
TOPIC 10- GASTRULATION, THE FORMATION OF THE TRILAMINAR GERM DISC.
FORMATION OF NOTOCHORD.
GASTRULATION
• The most characteris c event occurring during the third week of gesta on is gastrula on, the process
that establishes all three germ layers (ectoderm, mesoderm, and endoderm) in the embryo.
• Primi ve streak:
o Gastrula on begins with forma on of the primi ve streak on the surface of the epiblast
o Ini ally, the streak is vaguely de ned, but in a 15- to 16-day embryo, it is clearly visible as a
narrow groove with slightly bulging regions on either side.
o The cephalic end of the streak, the primi ve node, consists of a slightly elevated area
surrounding the small primi ve pit
• Invagina on:
o Cells of the epiblast migrate toward the primi ve streak
o Upon arrival in the region of the streak, they become ask-shaped, detach from the epiblast,
and slip beneath it. This inward movement is known as invagina on.
• Control of cell migra on and speci ca on:
o This is done by broblast growth factor 8 (FGF8), which is synthesized by streak cells
themselves.
o This growth factor controls cell movement by down-regula ng E-cadherin, a protein that
normally binds epiblast cells together.
o FGF8 then controls cell speci ca on into the mesoderm by regula ng brachyury(T) expression.
• Once the cells have invaginated,
o some displace the hypoblast, crea ng the embryonic endoderm,
o and others come to lie between the epiblast and newly created endoderm to form mesoderm.
o Cells remaining in the epiblast then form ectoderm.
o Thus, the epiblast, through the process of gastrula on, is the source of all of the germ layers,
and cells in these layers will give rise to all of the ssues and organs in the embryo.
• Further migra on:
o As more and more cells move between the epiblast and hypoblast layers, they begin to spread
laterally and cranially.
o Gradually, they migrate beyond the margin of the disc and establish contact with the
extraembryonic mesoderm covering the yolk sac and amnion.
o In the cephalic direc on, they pass on each side of the prechordal plate.
• What is the prechordal plate?
o It forms between the p of the notochord and the oropharyngeal membrane
o It is derived from some of the rst cells that migrate through the node in the midline and move
in a cephalic direc on.
o It will be important for induc on of the forebrain.
• What is oropharyngeal membrane?
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 o It is at the cranial end of the disc
o It consists of a small region of ghtly adherent ectoderm and endoderm cells
o It represents the future opening of the oral cavity
FORMATION OF THE NOTOCHORD
• Prenotochordal cells ! notochordal plate ! de ni ve notochord
o Prenotochordal cells invagina ng in the primi ve node move forward cranially in the midline
un l they reach the prechordal plate.
o These prenotochordal cells become intercalated in the hypoblast so that for a short me, the
midline of the embryo consists of two cell layers that form the notochordal plate.
o As the hypoblast is replaced by endoderm cells, cells of the notochordal plate proliferate and
detach from the endoderm.
o They then form a solid cord of cells, the de ni ve notochord, which
▪ underlies the neural tube
▪ and is a signaling center for inducing the axial skeleton.
•
• Elonga on:
o Because elonga on of the notochord is a dynamic process, the cranial end forms rst, and
caudal regions are added as the primi ve streak assumes a more caudal posi on.
o The notochord and prenotochordal cells extend cranially to the prechordal plate and caudally to
the primi ve pit.
• The Neurenteric canal:
o Formed at the point where the pit forms an indenta on in the epiblast,
o temporarily connects the amnio c and yolk sac cavi es.
• The cloacal membrane:
o Is formed at the caudal end of the embryonic disc
o It is similar in structure to the oropharyngeal membrane,
o consists of ghtly adherent ectoderm and endoderm cells with no intervening mesoderm.
• The allantois:
o When the cloacal membrane appears, the posterior wall of the yolk sac forms a small
diver culum that extends into the connec ng stalk.
o This diver culum, the allantoenteric diver culum, or allantois, appears around the 16th day of
development
o Although in some lower vertebrates, the allantois serves as a reservoir for excre on products of
the renal system, in humans, it remains rudimentary but may be involved in abnormali es of
bladder development
TOPIC 11- DIFFERENTIATION OF ECTODERM AND ITS DERIVATIVES. NEURULATION.
• At the beginning of the third week of development, the ectodermal germ layer has the shape of a disc
that is broader in the cephalic than in the caudal region.
• Appearance of the notochord and prechordal mesoderm induces the overlying ectoderm to thicken and
form the neural plate
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 • Cells of the plate make up the neuroectoderm, and their induc on represents the ini al event in the
process of neurula on.
MOLECULAR REGULATION OF NEURAL INDUCTION
• Upregula on of broblast growth factor (FGF) signaling together with inhibi on of the ac vity of bone
morphogene c protein 4 (BMP4), a transforming growth factor-B (TGF-B) family member responsible
for ventralizing ectoderm and mesoderm, causes induc on of (=directs the development of) the neural
plate.
• FGF signaling:
o probably promotes a neural pathway by an unknown mechanism
o represses BMP transcrip on
o upregulates expression of CHORDIN and NOGGIN, which inhibit BMP ac vity.
• In the presence of BMP4,
o ectoderm is induced to form epidermis;
o and mesoderm forms intermediate and lateral plate mesoderm.
• Without BMPs,
o ectoderm become neural ssue.
o mesoderm to become notochord and paraxial mesoderm
• Secre on of three other molecules, noggin, chordin, and follista n, inac vates BMP.
• These three proteins are present in the organizer (primi ve node), notochord, and prechordal
mesoderm.
• However, these neural inducers induce only forebrain and midbrain types of ssues (cranial neural plate
structures).
• Induc on of caudal neural plate structures (hindbrain and spinal cord) depends on two secreted
proteins, WNT3a and FGF.
• In addi on, re noic acid (RA) appears to play a role in organizing the cranial-to-caudal axis
NEURULATION
• NOTE: The PCP pathway regulates the process of convergent extension, whereby a ssue becomes
longer and narrower
• Neurula on is the process whereby the neural plate forms the neural tube.
• One of the key events in this process is lengthening of the neural plate and body axis by the
phenomenon of convergent extension, whereby there is a lateral to medial movement of cells in the
plane of the ectoderm and mesoderm.
• The process is regulated by signaling through the planar cell polarity pathway.
• As the neural plate lengthens, its lateral edges elevate to form neural folds, and the depressed mid
region forms the neural groove.
• Gradually, the neural folds approach each other in the midline, where they fuse.
• Fusion begins in the cervical region ( h somite) and proceeds cranially and caudally
• As a result, the neural tube is formed.
• Un l fusion is complete, the cephalic and caudal ends of the neural tube communicate with the
amnio c cavity through the anterior (cranial) and posterior (caudal) neuropores

cranial neuropore day 25 18- to 20-somite stage

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 posterior neuropore day 28 25-somite stage
Closure of neuropores:

• Neurula on is then complete, and the central nervous system is represented by:
o a closed tubular structure with a narrow caudal por on, the spinal cord,
o a much broader cephalic por on characterized by a number of dila ons, the brain vesicles
TOPIC 12 - DIFFERENTIATION OF ECTODERM AND ITS DERIVATIVES. NEURAL CREST AND
ITS DERIVATIVES. DEFINITION AND SIGNIFICANCE IN DEVELOPMENT OF EPITHELO-
MESENCHYMAL AND MESENCHYMAL-EPITHELIAL TRANSITIONS.
NEURAL CREST CELLS
• As the neural folds elevate and fuse, cells at the lateral border or crest of the neuroectoderm begin to
dissociate from their neighbors.
• This cell popula on, the neural crest cells (NCC) undergoes an epithelial-to-mesenchymal transi on as
it leaves the neuroectoderm to enter the underlying mesoderm.
• (Mesoderm refers to cells derived from the epiblast and extraembryonic ssues. Mesenchyme refers to
loosely organized embryonic connec ve ssue regardless of origin.)
• Crest cells from the trunk region leave the neuroectoderm a er closure of the neural tube and migrate
along one of two pathways:
o (1) a dorsal pathway through the dermis, where they will enter the ectoderm through holes in
the basal lamina to form melanocytes in the skin and hair follicles,
o (2) a ventral pathway through the anterior half of each somite to become sensory ganglia,
sympathe c and enteric neurons, Schwann cells, and cells of the adrenal medulla.
• NCC also form and migrate from cranial neural folds, leaving the neural tube before closure in this
region.
o These cells contribute to the craniofacial skeleton as well as neurons for cranial ganglia, glial
cells, melanocytes, odontoblasts, and other cell types
• NCC are so fundamentally important and contribute to so many organs and ssues that they are
some mes referred to as the fourth germ layer.
• They are also involved in at least one-third of all birth defects and many cancers, such as melanomas,
neuroblastomas, and others.
MOLECULAR REGULATION OF NEURAL CREST INDUCTION
• The fate of the en re ectodermal germ layer depends on BMP concentra ons:
o High levels induce epidermis forma on
o Intermediate levels, at the border of the neural plate and surface ectoderm, induce the neural
crest
o Very low concentra ons cause forma on of neural ectoderm
• The proteins noggin and chordin regulate the concentra ons of BMP by ac ng as BMP inhibitors.
• The intermediate concentra ons of BMPs, together with FGF and WNT proteins, induce PAX3 and
other transcrip on factors that “specify” the neural plate border. In turn, these transcrip on factors
induce a second wave of transcrip on factors, including:
o SNAIL and FOXD3, which specify cells as neural crest,
o and SLUG, which promotes crest cell migra on from the neuroectoderm.
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 EPITHELO-MESENCHYMAL AND MESENCHYMAL-EPITHELIAL TRANSITIONS
• The neural crest cells (NCC) undergo an epithelial-to-mesenchymal transi on as they leave the
neuroectoderm to enter the underlying mesoderm.
• Cells of the somites undergo a process of epitheliza on and arrange themselves in a donut shape
around a small lumen. Cells in the ventral and medial walls of the somite lose their epithelial
characteris cs, become mesenchymal ( broblast-like) again to form the sclerotome. Cells from both
muscle precursor groups become mesenchymal again and migrate beneath the dermatome to create
the dermomyotome.
• Di eren a on of structures derived from pharyngeal arches, pouches, cle s, and prominences is
dependent on epithelial-mesenchymal interac ons.
• Some epicardial cells undergo an epithelial- to-mesenchymal transi on induced by the underlying
myocardium. The newly formed mesenchymal cells then contribute to endothelial and smooth muscle
cells of the coronary arteries.
• Branching (of the bronchial tree) is regulated by epithelial-mesenchymal interac ons between the
endoderm of the lung buds and visceral mesoderm that surrounds them.
• Teeth themselves arise from an epithelial-mesenchymal interac on between overlying oral epithelium
and underlying mesenchyme derived from neural crest cells.
TOPIC 13 - DIFFERENTIATION OF ECTODERM AND ITS DERIVATIVES. PLACODS AND ITS
DERIVATIVES. ECTOMESENCHYME
PLACODS
• By the me the neural tube is closed, two bilateral ectodermal thickenings, the o c placodes and the
lens placodes, become visible in the cephalic region of the embryo
• During further development, the o c placodes invaginate and form the o c vesicles, which will develop
into structures needed for hearing and maintenance of equilibrium.
• At approximately the same me, the lens placodes appear. These placodes also invaginate and, during
the h week, form the lenses of the eyes.
• In general terms, the ectodermal germ layer gives rise to organs and structures that maintain contact
with the outside world:
o The central nervous system
o The peripheral nervous system
o The sensory epithelium of the ear, nose, and eye
o The epidermis, including the hair and nails
• In addi on, it gives rise to the following:
o The subcutaneous glands
o The mammary glands
o The pituitary gland
o Enamel of the teeth
ECTOMESENCHYME
• It is a form of mesenchyme, in the embryo, consis ng of neural crest cells
• It plays a cri cal role in the forma on of the hard and so ssues of the head and neck such as bones,
muscles, teeth and, notably, the pharyngeal arches.
TOPIC 14 - DIFFERENTIATION AND DERIVATIVES OF INTRAEMBRYONIC MESODERM.
PARAXIAL MESODERM.
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 • Ini ally, cells of the mesoderm form a thin sheet of loose ssue on each side of the midline.
• By approximately the 17th day, however, cells close to the midline proliferate and form a thickened
plate of ssue known as paraxial mesoderm.
• More laterally, the mesoderm layer remains thin and is known as the lateral plate.
• Intercellular cavi es appear within the lateral plate, and fuse, thus dividing the ssue into two layers:
o A layer con nuous with mesoderm covering the amnion, known as the soma c or parietal
mesoderm layer
o A layer con nuous with mesoderm covering the yolk sac, known as the splanchnic or visceral
mesoderm layer
• Together, these layers line a newly formed cavity, the intraembryonic cavity, which is con nuous with
the extraembryonic cavity on each side of the embryo.
• Intermediate mesoderm connects paraxial and lateral plate mesoderm
PARAXIAL MESODERM
• By the beginning of the third week, paraxial mesoderm begins to be organized into segments.
• These segments, known as somitomeres,
o First appear in the cephalic region of the embryo, and their forma on proceeds cephalocaudally.
o Each consists of mesodermal cells arranged in concentric whorls around the center of the unit.
o In the head region, they form in associa on with neuromeres (segmenta on of the neural plate)
and contribute to mesenchyme in the head.
• Somites:
o From the occipital region caudally, somitomeres further organize into somites.
o The rst pair of somites arises in the occipital region of the embryo at approximately the 20th
day of development.
o From here, new somites appear in craniocaudal sequence
• How many?
o at a rate of approximately three pairs per day un l, at the end of the h week, 42 to 44 pairs
are present
o There are 4 occipital, 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 8 to 10 coccygeal pairs.
o The rst occipital and the last ve to seven coccygeal somites later disappear, whereas the
remaining somites form the axial skeleton.
• Because somites appear with a speci ed periodicity, the age of an embryo can be accu- rately
determined during this early me period by coun ng somites.
MOLECULAR REGULATION OF SOMITE FORMATION
• The regulatory genes include members of the NOTCH and WNT signaling pathways
• Overlapping expression gradients:
o Re noic Acid RA (regulates the boundary of each somite) is expressed at high concentra ons
cranially and decreases in concentra on caudally,
o whereas the combina on of FGF8 and WNT3a proteins is expressed at higher concentra ons
caudally and lower concentra ons cranially
SOMITE DIFFERENTIATION
• Each somite forms its own:
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 o sclerotome (the tendon car lage and bone component),
o myotome (providing the segmental muscle component),
o dermatome, which forms the dermis of the back.
• Each myotome and dermatome also has its own segmental nerve component
• When somites rst form from presomi c mesoderm, they exist as a ball of mesoderm ( broblast-like)
cells.
• These cells then undergo a process of epitheliza on and arrange themselves in a donut shape around a
small lumen.
• By the beginning of the fourth week,
o cells in the ventral and medial walls of the somite lose their epithelial characteris cs, become
mesenchymal ( broblast-like) again, and shi their posi on to surround the neural tube and
notochord. Collec vely, these cells form the sclerotome that will di eren ate into the vertebrae
and ribs.
o Cells at the dorsomedial and ventrolateral edges of the upper region of the somite form
precursors for muscle cells,
o whereas cells between these two groups form the dermatome.
• Cells from both muscle precursor groups become mesenchymal again and migrate beneath the
dermatome to create the dermomyotome.
o Cells in the dermomyotome ul mately form dermis for the skin of the back and muscles for the
back, body wall (intercostal muscles), and some limb muscles
• In addi on, cells from the ventrolateral edge migrate into the parietal layer of lateral plate mesoderm,
to form most of the musculature for the body wall and most of the limb muscles.
• At the end of the 4th week, sclerotome cells become polymorphous and form loosely organized ssue,
called mesenchyme, embryonic connec ve ssue. This mesenchyme can di eren ate in many ways.
They may become bro-, chondro-, or osteo- blasts.
TOPIC 15 - DIFFERENTIATION AND DERIVATIVES OF INTRAEMBRYONIC MESODERM.
INTERMEDIATE AND LATERAL PLATE MESODERM. EARLY STEPS OF THE FORMATION OF
INTRAEMBRYONIC BODY CAVITIES. TERATOGENICITY.
INTERMEDIATE MESODERM
• Intermediate mesoderm, which temporarily connects paraxial mesoderm with the lateral plate,
di eren ates into urogenital structures.
o In cervical and upper thoracic regions, it forms segmental cell clusters (future nephrotomes)
o more caudally, it forms an unsegmented mass of ssue, the nephrogenic cord.
• Excretory units of the urinary system and the gonads develop from this partly segmented, partly
unsegmented intermediate mesoderm.
LATERAL PLATE MESODERM
• Lateral plate mesoderm splits into parietal (soma c) and Visceral (splanchnic) layers, which line the
intraembryonic cavity and surround the organs, respec vely
• Parietal Layer:
o Mesoderm from the parietal layer, together with overlying ectoderm, forms the lateral body
wall folds.
▪ These folds, together with the head (cephalic) and tail (caudal) folds, close the ventral
body wall.
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 ▪ The parietal layer of lateral plate mesoderm then forms the dermis of the skin in the
body wall and limbs, the bones and connec ve ssue of the limbs, and the sternum.
o Mesoderm from the parietal layer surrounding the intraembryonic cavity form the mesothelial
membranes, or serous membranes, which will line the peritoneal, pleural, and pericardial
cavi es and secrete serous uid
o In addi on, sclerotome and muscle precursor cells that migrate into the parietal layer of lateral
plate mesoderm form the costal car lages, limb muscles, and most of the body wall muscles
• The visceral layer:
o The visceral layer of lateral plate mesoderm, together with embryonic endoderm, forms the wall
of the gut tube
o Mesoderm cells of the visceral layer form a thin serous membrane around each organ
• Blood cells and blood vessels also arise from mesoderm.
• Blood vessels form in two ways:
o Vasculogenesis, whereby vessels arise from blood islands
o Angiogenesis, which entails sprou ng from exis ng vessels.
• Mesoderm cells are induced to form hemangioblasts (a common precursor for vessel and blood cell
forma on.)
• From these, the rst blood islands appear in mesoderm surrounding the wall of the yolk sac at 3 weeks
of development and slightly later in lateral plate mesoderm and other regions.
• However, this popula on is transitory. The de ni ve hematopoie c stem cells are derived from
mesoderm surrounding the aorta in a site near the developing mesonephric kidney called the aorta-
gonad-mesonephros region (AGM).
INTRA EMBRYONIC BODY CAVITIES
• The visceral layer of lateral plate mesoderm rolls ventrally and is in mately connected to the gut tube;
the parietal layer, together with the overlying ectoderm, forms the lateral body wall folds (one on each
side of the embryo), which move ventrally and meet in the midline to close the ventral body wall.
• The space between visceral and parietal layers of lateral plate mesoderm is the primi ve body cavity,
which at this early stage is a con nuous cavity, because it has not yet been subdivided into the
pericardial, pleural, and abdominopelvic regions.
• Soon a er it forms as a solid mesodermal layer, cle s appear in the lateral plate mesoderm that
coalesce to split the solid layer into two:
o (1) the parietal (soma c) layer adjacent to the surface ectoderm and con nuous with the extra-
embryonic parietal mesoderm layer over the amnion. Together, the parietal (soma c) layer of
lateral plate mesoderm and overlying ectoderm are called the somatopleure
o (2) the visceral (splanchnic) layer adjacent to endoderm forming the gut tube and con nuous
with the visceral layer of extraembryonic mesoderm covering the yolk sac. Together, the visceral
(splanchnic) layer of lateral plate mesoderm and underlying endoderm are called the
splanchnopleure.
• Some cells of the parietal layer of lateral plate mesoderm lining the body wall of the primi ve
embryonic cavity become mesothelial and form the parietal layer of the serous membranes lining the
outside of the peritoneal, pleural, and pericardial cavi es. (see topics 19 & 20 in systems)
• Teratogenicity – topic 8
TOPIC 16 - DIFFERENTIATION AND DERIVATIVES OF THE ENDODERM.
• The gastrointes nal tract is the main organ system derived from the endodermal germ layer.
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 • This germ layer covers the ventral surface of the embryo and forms the roof of the yolk sac.
• With development and growth of the brain vesicles, however, the embryonic disc begins to bulge into
the amnio c cavity.
o Lengthening of the neural tube now causes the head and tail folds to move ventrally.
o Two lateral body wall folds form and also move ventrally to close the ventral body wall.
o The amnion is pulled down, such that the embryo lies within the amnio c cavity
o The ventral body wall closes completely except for the umbilical region where the connec ng
stalk and yolk sac duct remain a ached.
• NOTE:
o Sagi al midline sec ons demonstrate cephalocaudal folding
o Cross sec ons demonstrate lateral folding
• As a result of cephalocaudal growth and closure of the lateral body wall folds, a con nuously larger
por on of the endodermal germ layer is incorporated into the body of the embryo to form the gut
tube.
• The tube is divided into three regions: the foregut, midgut, and hindgut
• The midgut communicates with the yolk sac by way of a broad stalk, the Vitelline (yolk sac) duct. This
duct is wide ini ally, but with further growth of the embryo, it becomes narrow and much longer.
• At its cephalic end, the foregut is temporarily bounded by an ectodermal-endodermal membrane called
the oropharyngeal membrane.
o This membrane separates the stomodeum, the primi ve oral cavity (derived from ectoderm),
from the pharynx, (a part of the foregut derived from endoderm).
o In the fourth week, the oropharyngeal membrane ruptures, establishing an open connec on
between the oral cavity and the primi ve gut.
• The hindgut also terminates temporarily at an ectodermal-endodermal membrane, the cloacal
membrane
o This membrane separates the upper part of the anal canal, derived from endoderm, from the
lower part, called the proctodeum, which is formed by ectoderm.
o The membrane breaks down in the seventh week to create the opening for the anus.
• Another important result of cephalocaudal growth and lateral folding is par al incorpora on of the
allantois into the body of the embryo, where it forms the cloaca.
• The distal por on of the allantois remains in the connec ng stalk.
• By the h week, the yolk sac duct, allantois, and umbilical vessels are restricted to the umbilical region
• Hence, the endodermal germ layer ini ally forms the epithelial lining of the primi ve gut and the
intraembryonic por ons of the allantois and vitelline duct.
• During further development, endoderm gives rise to the following:
o The epithelial lining of the respiratory tract
o The parenchyma of the thyroid, parathyroids, liver, and pancreas
o The re cular stroma of the tonsils and the thymus
o The epithelial lining of the urinary bladder and the urethra
o The epithelial lining of the tympanic cavity and auditory tube
TOPIC 17 - DEFINITION OF ORGANOGENESIS. CEPHALO-CAUDAL AND LATERAL FOLDING OF
THE EMBRYO.
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• The period of organogenesis or the embryonic period, is the period of development when the organ
primordia are established, usually considered to be from the beginning of the third week to the end of
the eighth week of gesta on. This is the me when organs are most sensi ve to insult, and induc on of
most birth defects occurs.
FOLDING
• During the fourth week, the sides of the embryo begin to grow ventrally forming two lateral body wall
folds. These folds consist of the parietal layer of lateral plate mesoderm, overlying ectoderm, and cells
from adjacent somites that migrate into the mesoderm layer.
• As these folds progress, the endoderm layer also folds ventrally and closes to form the gut tube.
• By the end of the fourth week, the lateral body wall folds meet in the midline and fuse to close the
ventral body wall. This closure is aided by growth of the head and tail regions (folds) that cause the
embryo to curve into the fetal posi on.
• Closure of the ventral body wall is complete except in the region of the connec ng stalk (future
umbilical cord). Similarly, closure of the gut tube is complete except for a connec on from the midgut
region to the yolk sac called the Vitelline (yolk sac) duct
TOPIC 18 - FOETAL DEVELOPMENT (CHANGES OF THE EXTERNAL FEATURES). EXTERNAL
FEATURES OF THE MATURE FOETUS (NEWBORN).
SECOND MONTH
• The age of the embryo:
o Is expressed in somites un l 2nd month
o From the second month of development, the age of the embryo is indicated as the crown-rump
length (CRL) and expressed in millimetes.
▪ CRL is the measurement from the vertex of the skull to the midpoint between the apices
of the bu ocks.
• At the end of the fourth week, the embryo has approximately 28 somites. In the 5th week, the CRL is 5-8
mm.
• During this month,
o the main external features are the somites and pharyngeal arches
o the external appearance of the embryo is changed by an increase in head size and forma on of
the limbs, face, ears, nose, and eyes.
• Appearance of limbs:
• By the beginning of the h week, forelimbs and hind limbs appear as paddle-shaped buds.
• The forelimbs are located dorsal to the pericardial swelling at the level of the fourth cervical to the rst
thoracic somites, (which explains their innerva on by the brachial plexus.)
• Hind limb buds appear slightly later just caudal to a achment of the umbilical stalk at the level of the
lumbar and upper sacral somites.
• With further growth, the terminal por ons of the buds a en, and a circular constric on separates
them from the proximal, more cylindrical segment.
• Soon, four radial grooves separa ng ve slightly thicker areas appear on the distal por on of the buds,
foreshadowing forma on of the digits.
• These grooves, known as rays, appear in the hand region rst and shortly a erward in the foot, as the
upper limb is slightly more advanced in development than the lower limb.
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 • While ngers and toes are being formed, a second constric on divides the proximal por on of the buds
into two segments, and the three parts characteris c of the adult extremi es can be recognized.
THIRD MONTH
• At the beginning of the third month, the head cons tutes approximately half of the CRL
• Face- more human looking
• Eyes- ini ally directed laterally, move to the ventral aspect of the face,
• Ears- come to lie close to their de ni ve posi on at the side of the head
• Limbs- reach their rela ve length in comparison with the rest of the body,
• By the 12th week:
• Primary ossi ca on centers- are present in the long bones and skull
• External genitalia develop to such a degree that the sex of the fetus can be determined by external
examina on (ultrasound).
• Intes nal loops have withdrawn into the abdominal cavity. (During the 6th week, intes nal loops cause
a large swelling (hernia on) in the umbilical cord)
• At the end of the third month, re ex ac vity can be evoked in aborted fetuses, indica ng muscular
ac vity.
FOURTH AND FIFTH MONTH
• By the beginning of the h month, the size of the head is about one-third of the CHL.
• During the fourth and h months, the fetus lengthens rapidly, and at the end of the rst half of
intrauterine life, its CRL is approximately 15 cm
• The weight of the fetus increases li le during this period and by the end of the h month is s ll <
500g.
• The fetus is covered with ne hair, called lanugo hair; eyebrows and head hair are also visible.
• During the h month, movements of the fetus can be felt by the mother.
• During the second half of intrauterine life, weight increases considerably, par cularly during the last 2.5
months, when 50% of the full-term weight (approximately 3,200 g) is added.
• During the sixth month, the skin of the fetus is reddish and has a wrinkled appearance because of the
lack of underlying connec ve ssue.
• A fetus born early in the sixth month has great di culty surviving. Although several organ systems are
able to func on, the respira- tory system and the central nervous system have not di eren ated
su ciently, and coordina on between the two systems is not yet well established.
SIXTH AND SEVENTH MONTH
• By 6.5 to 7 months, the fetus has a CRL of about 25 cm and weighs approximately 1,100 g. If born at this
me, the infant has a 90% chance of surviving.
• Some developmental events occurring during the rst 7 months:
o Taste buds appear
o Swallowing
o Respiratory movements
o Sucking movements
o Some sounds can be heard
o Eyes sensi ve to light
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 EIGHTH AND NINTH MONTH
• The period from the beginning of the ninth week to birth is known as the fetal period
• During the last 2 months, the fetus obtains well-rounded contours as the result of deposi on of
subcutaneous fat.
• By the end of intrauterine life, the skin is covered by a whi sh, fa y substance (vernix caseosa)
composed of secretory products from sebaceous glands.
• At the end of the ninth month, the skull has the largest circumference of all parts of the body, an
important fact with regard to its passage through the birth canal.
• At the me of birth,
o Size of the head is one-quarter of the CHL
o Weight of a normal fetus is 3,000 to 3,400 g
o CRL is about 36 cm
o CHL is about 50 cm.
o Sexual characteris cs are pronounced, and the testes should be in the scrotum.
• NOTE:
o crown-rump length (CRL) (si ng height)
o crown- heel length (CHL) (standing height)
▪ The measurement from the vertex of the skull to the heel
TOPIC 19 - FOETAL MEMBRANES, AMNIOTIC FLUID. LANUGO FETALIS, VERNIX CASEOSA.
TWIN PREGNANCY.
AMNIOTIC FLUID
• The amnio c cavity is lled with a clear, watery uid, the amnio c uid.
• It is produced in part by amnio c cells but is derived primarily from maternal blood.
• During the early months of pregnancy, the embryo is suspended by its umbilical cord in this uid
• The uid serves as a protec ve cushion. It:
o (1) absorbs jolts,
o (2) prevents adherence of the embryo to the amnion
o (3) allows for fetal movements.
• The amount of uid increases from approximately 30 mL at 10 weeks of gesta on to 450 mL at 20
weeks to 800 to 1,000 mL at 37 weeks.
• The volume of amnio c uid is replaced every 3 hours.
• From the beginning of the h month, the fetus swallows its own amnio c uid. Fetal urine is added
daily to the amnio c uid in the h month, but this urine is mostly water because the placenta is
func oning as an exchange for metabolic wastes.
• During childbirth, the amniochorionic membrane forms a hydrosta c wedge that helps to dilate the
cervical canal.
FETAL MEMBRANES IN TWINS
• DIZYGOTIC TWINS
• Approximately 90% of twins are dizygo c, or fraternal, and their incidence increases with maternal age
and with fer lity procedures.
• They result from simultaneous shedding of two oocytes and fer liza on by di erent spermatozoa.
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 • Because the two zygotes have di erent gene c cons tu ons, the twins have no more resemblance
than any other brothers or sisters. They may or may not be of di erent sex.
• The zygotes implant individually in the uterus, and usually each develops its own placenta, amnion, and
chorionic sac.
• Some mes, however, the two placentas are so close together that they fuse. Similarly, the walls of the
chorionic sacs may also come into close apposi on and fuse.
• Occasionally, each dizygo c twin possesses red blood cells of two di erent types (erythrocyte
mosaicism), indica ng that fusion of the two placentas was so in mate that red cells were exchanged.
• MONOZYGOTIC TWINS
• Develop from a single fer lized ovum. The rate for monozygo c twins is 3 to 4 per 1,000. They result
from spli ng of the zygote at various stages of development. Twins are iden cal.
• CASE 1 - separa on occurs at the two-cell stage
o two separate zygotes develop.
o The blastocysts implant separately, and each embryo has its own placenta and chorionic sac.
o Although the arrangement of the membranes of these twins resembles that of dizygo c twins,
the two can be recognized as partners of a monozygo c pair by their strong resemblance in
blood groups, ngerprints, sex, and external appearance.
• CASE 2- Spli ng of the zygote usually occurs at the early blastocyst stage.
o The inner cell mass splits into two separate groups of cells within the same blastocyst cavity.
o The two embryos have a common placenta and a common chorionic cavity but separate
amnio c cavi es.
• CASE 3 - In rare cases, the separa on occurs at the bilaminar germ disc stage, just before the
appearance of the primi ve streak.
o This method of spli ng results in forma on of two partners with a single placenta and a
common chorionic and amnio c sac.
o Although the twins have a common placenta, blood supply is usually well balanced.
LANUGO FETALIS AND VERNIX CASEOSA
• Hairs that develop from downgrowth of epidermal cells into the underlying dermis are called lanugo
hair
• By the end of the third month, the rst hairs appear on the surface in the region of the eyebrow and
upper lip. By about 20 weeks, the fetus is covered by the lanugo hair
• The rst hair that appears, lanugo hair, is shed at about the me of birth and is later replaced by
coarser hairs arising from new hair follicles.
• By the end of intrauterine life, the skin is covered by a whi sh, fa y substance (vernix caseosa)
composed of secretory products from sebaceous glands.
• It is thought to have some protec ve roles during fetal development and for a few hours a er birth
TOPIC 20 - HEMOPOIESIS BEFORE AND AFTER BIRTH. ERYTHROPOIESIS. FORMATION OF
MEGAKARYOCYTES.
• Hemopoiesis (hematopoiesis) includes both erythropoiesis and leukopoiesis, as well as thrombopoiesis.
• Erythrocyte life span - 120 days, platelet life span -10 days.
• In the adult, erythrocytes, granulocytes, monocytes, and platelets are formed in the red bone marrow;
lymphocytes are also formed in the red bone marrow and in the lympha c ssues.
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 HEMOPOIESIS BEFORE BIRTH
• The rst phase or yolk-sac phase
o begins in the third week of gesta on
o is characterized by the forma on of “blood islands” in the wall of the yolk sac of the embryo.
• The second, or hepa c phase
o hemopoie c centers appear in the liver
o Blood cell forma on in these sites is largely limited to erythroid cells although some
leukopoiesis occurs in the liver.
o The liver is the major blood-forming organ in the fetus during the second trimester.
• The third or bone marrow phase
o involves the bone marrow (and other lympha c ssues) and begins during the second trimester
of pregnancy.
• The precursors of both the blood cells and germ cells arise in the yolk sac.
HEMOPOIESIS AFTER BIRTH
• According to the monophyle c theory of hemopoiesis blood cells are derived from a common
hemopoie c stem cell.
• Hemopoiesis is ini ated in an apparently random manner when individual HSCs begin to di eren ate
into one of the lineage-restricted progenitor cells.
• Progenitor cells have surface receptors for speci c cytokines and growth factors, including colony-
s mula ng factors (CSFs), that in uence their prolifera on and matura on into a speci c lineage.
• HSC
o CMP
▪ MEP
• MKP
• ErP
▪ GMP
• BMCP
• EoP
• NoP
• MoP
• DC
o CLP
▪ NK
▪ B
▪ T
DEVELOPMENT OF ERYTHROCYTES (ERYTHROPOIESIS)
• Erythrocyte development starts from CMP cells that, under the in uence of erythropoie n, IL-3, and
IL-4, di eren ate to MEP cells.
• Under GATA-1 (transcrip on factor) in uence, MEP cells transform into erythropoie n-sensi ve
erythrocyte- commi ed progenitors (ErPs or CFU-E) that give rise to the proerythroblast.
• The rst microscopically recognizable precursor cell in erythropoiesis is called the proerythroblast.
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 o The proerythroblast is a rela vely large cell measuring 12 to 20 micro meters in diameter. It
contains a large spherical nucleus with one or two visible nucleoli.
o The cytoplasm shows mild basophilia because of the presence of free ribosomes.
• The basophilic erythroblast is smaller than the proerythroblast, from which it arises by mito c
division.
o The nucleus of the basophilic erythroblast is smaller and progressively more heterochroma c with
repeated mitoses.
o The cytoplasm shows strong basophilia because of the large number of free ribosomes
(polyribosomes) that synthesize hemoglobin. The accumula on of hemoglobin in the cell gradually
changes the staining reac on of the cytoplasm so that it begins to stain with eosin.
o At the stage when the cytoplasm displays both acidophilia, because of the staining of hemoglobin,
and basophilia, because of the staining of the ribosomes, the cell is called a polychromatophilic
erythroblast.
• The polychromatophilic erythroblast shows both acidophilic and basophilic staining of cytoplasm.
o The staining reac ons of the polychromatophilic erythroblast may blend to give an overall gray or
lilac color to the cytoplasm, or dis nct pink (acidophilic) and purple (basophilic) regions may be
resolved in the cytoplasm.
o The nucleus of the cell is smaller than that of the basophilic erythroblast, and coarse
heterochroma n granules form a checkerboard pa ern that helps iden fy this cell type.
• The orthochromatophilic erythroblast (normoblast) is recognized by its increased acidophilic
cytoplasm and dense nucleus.
o This cell has a small, compact, densely stained nucleus. The cytoplasm is eosinophilic because of
the large amount of hemoglobin. It is only slightly larger than a mature erythrocyte. At this stage,
the orthochromatophilic erythroblast is no longer capable of division.
• The polychromatophilic erythrocyte (re culocytes) has extruded its nucleus.
o The orthochroma c erythroblast loses its nucleus by extruding it from the cell; it is then ready to
pass into the blood sinusoids of the red bone marrow. Some polyribosomes that can s ll
synthesize hemoglobin are retained in the cell. These polyribosomes impart a slight basophilia to
the otherwise eosinophilic cells; for this reason, these new cells are called polychromatophilic
erythrocytes.
• Erythrocytes have a life span of about 120 days in humans.
o When erythrocytes are about 4 months old, they become senescent. The macrophage system of
the spleen, bone marrow, and liver phagocytoses and degrades the senescent erythrocytes.
o The heme and globin dissociate, and the globin is hydrolyzed to amino acids, which enter the
metabolic pool for reuse.
o The iron on the heme is released, enters the iron-storage pool, and is stored for reuse in
hemoglobin synthesis. The rest of the heme moiety of the hemoglobin molecule is par ally
degraded to bilirubin
FORMATION OF MEGAKARYOCYTES
• The thrombocytopoiesis from the bone marrow progenitors is a complex process of cell divisions and
di eren a on that requires the support of interleukins, colony-s mula ng factors, and hormones.
• CMP stem cell di eren ates into a bipotent megakaryocyte/erythrocyte progenitor (MEP) cell.
• Further development proceeds toward a unipotent megakariocyte- commi ed progenitor (MKP) cell
(or CFU-Meg), which further develops into the megakaryoblast.
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 • The megakaryoblast that develops from this MKP is a large cell (about 30 micro.m in diameter) with a
nonlobed nucleus. No evidence of platelet forma on is seen at this stage.
• Successive endomitoses occur in the megakaryoblast (i.e., chromosomes replicate), but neither
karyokinesis nor cytokinesis occurs.
• Under s mula on by thrombopoie n, ploidy increases from 8n to 64n before chromosomal
replica on ceases. The cell then becomes a platelet-producing megakaryocyte, a cell measuring 50 to
70 micro.m in diameter with a complex mul lobed nucleus and sca ered azurophilic granules.
• Both the nucleus and the cell increase in size in propor on to the ploidy of the cell.
• The peripheral cytoplasm of the megakaryocyte appears to be divided into small compartments by
invagina on of the plasma membrane. These invagina ons are the platelet demarca on channels
TOPIC 21 - THROMBOPOIESIS. GRANULOPOIESIS. MONOPOIESIS. LYMPHOPOIESIS.
DEVELOPMENT OF THYMUS.
DEVELOPMENT OF GRANULOCYTES (GRANULOPOIESIS)
• Granulocytes originate from the mul poten al common myeloid progenitor (CMP) stem cell, which
di eren ates into granulocyte/monocyte progenitors (GMPs) under the in uence of cytokines such as
GM-CSF, granulocyte colony-s mula ng factor (G-CSF), and IL-3.
• The neutrophil progenitor (NoP) undergoes six morphologically iden able stages in the process of
matura on: myeloblast, promyelocyte, myelocyte, metamyelocyte, band cell, and mature neutrophil.
• Eosinophils and basophils undergo a morphologic matura on similar to that of neutrophils.
• In the presence of IL 5, GMP cells di eren ate to eosinophil progenitors (EoPs), and eventually mature
to eosinophils. Lack of IL-5 causes the GMP cells to di eren ate into basophil progenitors (BaPs), which
produce basophils.
• Myeloblasts are the rst recognizable cells that begin the process of granulopoiesis.
o The myeloblast is the earliest microscopically recognizable neutrophil precursor cell in the bone
marrow. It has a large, euchroma c, spherical nucleus with three to ve nucleoli.
o The small amount of agranular cytoplasm stains intensely basophilic. A Golgi area is o en seen
where the cytoplasm is unstained. The myeloblast matures into a promyelocyte.
• Promyelocytes are the only cells to produce azurophilic granules.
o The promyelocyte has a large spherical nucleus with azurophilic (primary) granules in the
cytoplasm. Azurophilic granules are produced only in promyelocytes; cells in subsequent stages of
granulopoiesis do not make azurophilic granules. For this reason, the number of azurophilic
granules is reduced with each division of the promyelocyte and its progeny. Promyelocytes do not
exhibit subtypes. Recogni on of the neutrophil, eosinophil, and basophil lines is possible only in
the next stage—the myelocyte—when speci c (secondary) and ter ary granules begin to form.
• Myelocytes rst exhibit speci c granules.
o Myelocytes begin with a more or less spherical nucleus that becomes increasingly
heterochroma c
o Speci c granules begin to emerge from the convex surface of the Golgi apparatus, whereas
azurophilic granules are seen at the concave side. The signi cance of this separa on is unclear.
Myelocytes con nue to divide and give rise to metamyelocytes.
• The metamyelocyte is the stage at which neutrophil, eosinophil, and basophil lines can be clearly
iden ed by the presence of numerous speci c granules.
o A few hundred granules are present in the cytoplasm of each metamyelocyte, and the speci c
granules of each variety outnumber the azurophilic granules.
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 o The nucleus becomes more heterochroma c, and an indenta on deepens to form a kidney bean–
shaped structure.
o Theore cally, the metamyelocyte stage in granulopoiesis is followed by the band stage and then
the segmented stage. Although these stages are obvious in the neutrophil line, they are rarely if
ever observed in the eosinophil and basophil lines in which the next easily recognized stages of
development are the mature eosinophil and mature basophil, respec vely.
• In the neutrophil line, the band (stab) cell precedes devel-opment of the rst dis nct nuclear lobes.
o The nucleus of the band (stab) cell is elongated and of nearly uniform width
o Nuclear constric ons then develop in the band neutrophil and become more prominent un l two
to four nuclear lobes are recognized; the cell is then considered a mature neutrophil, also called a
polymorphonuclear neutrophil or segmented neutrophil.
DEVELOPMENT OF MONOCYTES
• The mul poten al CMP stem cell also gives rise to the cells that develop along the monocyte–
macrophage pathway.
• Monocytes are produced in the bone marrow from a GMP stem cell that can mature into a monocyte or
another of the three granulocy c cell lines. In addi on, GMP gives rise to dendri c cells.
• The prolifera on and di eren a on of CMP into commi ed GMP is controlled by IL-3.
• The monocytes remain in the circula on for only about 16 hours before emigra ng to the ssues where
they di eren ate into ssue macrophages.
DEVELOPMENT OF LYMPHOCYTES (LYMPHOPOIESIS)
• Development and lineage commitment of CLP cells de- pend on the expression of variety of
transcrip on factors.
• Although lymphocytes con nuously proliferate in the peripheral lympha c organs, the bone marrow
remains the primary site of lymphopoiesis in humans.
• Progeny of the CLP cells that express GATA-3 transcrip on factor are des ned to become T
lymphocytes. These cells that express GATA-3 leave the bone marrow as pre–T lymphocytes and travel
to the thymus, where they complete their di eren a on and thymic cell educa on. They then enter
the circula on as long-lived, small T lymphocytes.
• Another transcrip on factor, Pax5, ac vates B-cell–speci c genes in CLP cells des ned to become B
lymphocytes. In mammals, these cells originate in bursa-equivalent organs such as the bone marrow,
gut-associated lympha c ssue, and spleen.
DEVLOPMENT OF THYMUS
• Epithelium of the dorsal region of the third pharyngeal pouch di eren ates into the inferior parathyroid
gland, whereas the ventral region forms the thymus.
• Both gland primordia lose their connec on with the pharyngeal wall, and the thymus then migrates in a
caudal and a medial direc on, pulling the inferior parathyroid with it.
• Although the main por on of the thymus moves rapidly to its nal posi on in the anterior part of the
thorax where it fuses with its counterpart from the opposite side, its tail por on some mes persists
either embedded in the thyroid gland or as isolated thymic nests.
• Growth and development of the thymus con nue un l puberty.
• In the young child, the thymus occupies considerable space in the thorax and lies behind the sternum
and anterior to the pericardium and great vessels.
• In older persons, it is di cult to recognize because it is atrophied and replaced by fa y ssue.
TOPIC 22 - DEVELOPMENT OF ENAMEL. DENTITION.
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 GENERAL:
• Teeth themselves arise from an epithelial-mesenchymal interac on between overlying oral epithelium
(ectodermal) and underlying mesenchyme derived from neural crest cells.
• By the sixth week of development, the basal layer of the epithelial lining of the oral cavity forms a C-
shaped structure, the dental lamina, along the length of the upper and lower jaws.
• BUD STAGE – 8 weeks
o This lamina subsequently gives rise to a number of dental buds, 10 in each jaw, which form the
primordia of the ectodermal components of the teeth.
• CAP STAGE – 10 weeks
o The deep surface of the buds invaginates, resul ng in the cap stage of tooth development
o Such a cap consists of an outer layer, the outer dental epithelium; an inner layer, the inner
dental epithelium; and a central core of loosely woven ssue, the stellate re culum.
o The mesenchyme, which originates in the neural crest in the indenta on, forms the dental
papilla
• BELL STAGE – 3 months
o As the dental cap grows and the indenta on deepens, the tooth takes on the appearance of a
bell
o Mesenchyme cells of the papilla adjacent to the inner dental layer di eren ate into
odontoblasts, which later produce den n.
• Dental papilla and dental sac (follicle) are deriva ves of the ectomesenchyme of the upper and lower
jaw (maxilla, mandible) primordia
DEVELOPMENT OF ENAMEL
• Epithelial cells of the inner dental epithelium di eren ate into ameloblasts.
• These cells produce long enamel prisms that are deposited over the den n.
• Furthermore, a cluster of these cells in the inner dental epithelium forms the enamel knot that
regulates early tooth development
• Enamel is rst laid down at the apex of the tooth and from here spreads toward the neck.
• When the enamel thickens, the ameloblasts retreat into the stellate re culum. Here they regress,
temporarily leaving a thin membrane (dental cu cle) on the surface of the enamel.
• A er erup on of the tooth, this membrane gradually sloughs o .
• Stages of enamel forma on
DENTITION
• Human beings form two sets of teeth during their life, a set of temporary milk or deciduous teeth
replaced by a set of permanent or adult teeth. This type of den on is called diphyodont.
• The erup on of deciduous or milk teeth occurs 6 to 24 months a er birth.
• Buds for the permanent teeth, which lie on the lingual aspect of the milk teeth, are formed during the
third month of development.
• These buds remain dormant un l approximately the sixth year of postnatal life. Then they begin to
grow, pushing against the under-side of the milk teeth and aiding in the shedding of them.
• As a permanent tooth grows, the root of the overlying deciduous tooth is resorbed by osteoclasts.
• Heterodont den on - An adult human has 32 permanent teeth which are of four di erent types
TOPIC 23 - DEVELOPMENT OF THE PARODONTIUM.
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 • Parodon um consists of the cementum, PDLs, alveolarbone and gingiva
• Dental sac gives rise to cementoblasts secre ng cementum, and the periodontal connec ve ssue
• Outside of the cement layer, mesenchyme gives rise to the periodontal ligament, which holds the tooth
rmly in posi on and func ons as a shock absorber.
• Details of these teeth topics 22, 23, 24 – notebook
TOPIC 24 - DEVELOPMENT OF THE DENTIN, CEMENTUM AND DENTAL PULP.
DENTINE
• Mesenchyme cells of the papilla adjacent to the inner dental layer di eren ate into odontoblasts,
which later produce den n.
• With thickening of the den n layer, odontoblasts retreat into the dental papilla, leaving a thin
cytoplasmic process (dental process) behind in the den n
• The odontoblast layer persists throughout the life of the tooth and con nuously provides preden n.
• The remaining cells of the dental papilla form the pulp of the tooth
CEMENTUM AND PULP
• Forma on of the root of the tooth begins when the dental epithelial layers penetrate into the
underlying mesenchyme and form the epithelial root sheath.
• Cells of the dental papilla lay down a layer of den n con nuous with that of the crown. As more and
more den n is deposited, the pulp chamber narrows and nally forms a canal containing blood vessels
and nerves of the tooth.
• Mesenchymal cells on the outside of the tooth and in contact with den n of the root di eren ate into
cementoblasts. These cells produce a thin layer of specialized bone, the cementum.
TOPIC 25 - DEVELOPMENT OF KIDNEYS, FORMATION OF UROPOIETIC (URINE PRODUCING)
ELEMENTS.
• Topics 29 and 30 from systems embryo
TOPIC 26 - DEVELOPMENT AND MATURATION OF LUNG TISSUE. RESPIRATORY DISTRESS
SYNDROME.
• Development of lungs – topic 18 in systems
MATURATION OF THE LUNGS
• Alveoli and capillaries:
o Up to the seventh prenatal month, the bronchioles divide con nuously into more and smaller canals
(canalicular phase) and the vascular supply increases steadily
o Terminal bronchioles divide to form respiratory bronchioles, and each of these divides into three to
six alveolar ducts.
o The ducts end in terminal sacs (primi ve alveoli) that are surrounded by at alveolar cells in close
contact with neighboring capillaries.
o By the end of the seventh month, su cient numbers of mature alveolar sacs and capillaries are
present to guarantee adequate gas exchange, and the premature infant is able to survive
o During the last 2 months of prenatal life and for several years therea er, the number of terminal
sacs increases steadily.
• Alveolar epithelial cells:
o In addi on, cells lining the sacs, known as type I alveolar epithelial cells, become thinner, so that
surrounding capillaries protrude into the alveolar sacs.
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 o This in mate contact between epithelial and endothelial cells makes up the blood—air barrier.
o Mature alveoli are not present before birth. In addi on to endothelial cells and at alveolar
epithelial cells, another cell type develops at the end of the sixth month. These cells, type II alveolar
epithelial cells, produce surfactant, a phospholipid-rich uid capable of lowering surface tension at
the air-alveolar interface.
• Surfactant:
o Before birth, the lungs are full of uid that contains a high chloride concentra on, li le protein,
some mucus from the bronchial glands, and surfactant from the alveolar epithelial cells (type II).
The amount of surfactant in the uid increases, par cularly during the last 2 weeks before birth.
o As concentra ons of surfactant increase during the 34th week of gesta on, some of this
phospholipid enters the amnio c uid and acts on macrophages in the amnio c cavity.
o Once “ac vated,” these macrophages migrate across the chorion into the uterus where they begin
to produce immune system proteins, including interleukin- 1B. Up- regula on of these proteins
results in increased produc on of prostaglandins that cause uterine contrac ons.
o Thus, there may be signals from the fetus that par cipate in ini a ng labor and birth.
• Respira on:
o Fetal breathing movements begin before birth and cause aspira on of amnio c uid. These
movements are important for s mula ng lung development and condi oning respiratory muscles.
o When respira on begins at birth, most of the lung uid is rapidly resorbed by the blood and lymph
capillaries, and a small amount is probably expelled via the trachea and bronchi during delivery.
o When the uid is resorbed from alveolar sacs, surfactant remains deposited as a thin phospholipid
coat on alveolar cell membranes. With air entering alveoli during the rst breath, the surfactant
coat prevents development of an air—water (blood) interface with high surface tension.
o Without the fa y surfactant layer, the alveoli would collapse during expira on (atelectasis).
o Respiratory movements a er birth bring air into the lungs, which expand and ll the pleural cavity.
• Growth of lungs:
o Although the alveoli increase somewhat in size, growth of the lungs a er birth is due primarily to an
increase in the number of respiratory bronchioles and alveoli.
o It is es mated that only one-sixth of the adult number of alveoli are present at birth. The remaining
alveoli are formed during the rst 10 years of postnatal life through the con nuous forma on of
new primi ve alveoli.
• RESPIRATORY DISTRESS SYNDROME:
o When surfactant is insu cient, the air-water [blood] surface membrane tension becomes high,
bringing great risk that alveoli will collapse during expira on.
o As a result, respiratory distress syndrome [RDS] develops. This is a common cause of death in the
premature infant.
o Treatment of preterm babies with ar cial surfactant as well as treatment of mothers with
premature labor with glucocor coids to s mulate surfactant produc on have reduced the mortality
associated with RDS.
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