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GASTRULATION - movement of cells by sheets or layers separating the

- movements that generate the form of the organism blastocoel
- morphogenetic movements of cells leading to - forms a blastodisc
- rearrangement and the formation of the germ
layers (ecto, meso, endo) Convergent extension
- after fertilization: radical rearrangement
- why rearrangement? Cells are placed in new
neighborhoods giving them a chance to interact
with one another in very specific ways influencing
each other’s development fate
- followed by all organism in a species

Different Morphogenetic Movements

Epiboly
- movement of sheets of cells which intend to cover
other cells
- animal pole
- tends to cover the whole embryo

Invagination
- infolding of layer/s of cells
Delamination

REPRESENTATIVE GASTRULATION PATTERNS

Sea Urchin (oligolecithal eggs)
Involution
- creeps along the inner layer
- inward movement
- inturning of cells
- movement of cells inward

Ingression
- inward movement of cells as individuals
- not all oligolecithal eggs will gastrulate this way
- movement of cells individually
- single layer of cells surrounding a blastocoel
- move out individually
- area of vegetal pole: flattening out of cells; indents a
little bit (invagination)
Convergent extension
- indention of the whole layer
- cells intercalate narrowing the tissue and moving it
- micromeres will separate from the rest of the layer
forward
because they will go inside; start to grow in; form
- whole mess of cells that will form a straight line
the skeleton of the organism
- intercalate with each other to form one long layer
- hyaline layer: keeps it in a ball shape
- causes the stretching or elongation of a structure
- micromeres separate from hyaline layer
- give the embryo an elongated shape
- micromeres will extend to the other side, forming the
primitive gut
Delamination
- micromeres: extending and pulling other cells to
- separation of cells as parallel sheets
reach the other side: what guides them?
- in megalecithal eggs
Fibronectin: guide cells as they migrate
- to create the epiblast and hypoblast
Assignment: what happens to the area kung saan
- hypoblast is formed from the lower cells to form a
nanggaling ung invaginated part? And what
new upper cells
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happens to the migrating cells when they reach

the other side?

- Archenteron is very prominent

- Blastocoel disappears

*bottle-shaped cells: are predetermined to sink in and

invaginate inside

Frog/amphibians (mesolecithal egg)

- different type of cleavage pattern

- first indication of gastrulation: indentation in
between the animal and vegetal pole
- first 3 or 4 cells: will start moving inside; pulling the
rest of the cells na kasama nila Bird/avian (megalecithal egg)
- very impt because these cells start gastrulation and - area opaca: point where the blastodisc is sitting on
begin to form the dorsal lip top of yolk
- midgastrula: Where first blood vessels of the organisms form
- area pellucida: light can penetrate
Where embryo forms
Cells divide and divide then they will spread to one
side: the future posterior side
Area will thicken: incipient primitive streak
Cells will again divide and divide then will spread
from posterior to anterior side
Primitive streak and whole cell elongates because
- more rapid movement towards the opposite side
the cells are dividing
- creates the archenteron/primitive gut
- creates an antero-posterior axis and ventral/dorsal
- Posterior: blastopore lip
- Cells migrating towards the anterior sort of feel
around: fibronectin
- In process of making archenteron, it is displaced in
the ventral side
- Cells forming the primitive gut cause the
lengthening of the shape of the embryo:
Chordamesoderm
- Dorsal lip and lateral lip extend to the ventral??
- Dorsal, ventral and lateral lip form a circle
- Epibolic movement: why more darker parts than
the previous picture
- Not only are the cells involuting, animal pole cells
are undergoing epiboly to cover the vegetal pole
cells
- Chordamesoderm undergoing convergent extension
- late gastrula
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Analogy in the frog

- pero sa frog, involution hindi ingression ang
nangyayari
- Primitive streak: elongated blastopore
Hensen’s node: like a dorsal lip
- Dahil nga massive ang yolk sa frog: little movements
Avian: mas marami movements kc less yolk
(nakahiwalay ang yolk)
- Primitive streak will gradually shorten: will regress
fully
- Where first hypoblast fell: indication of the future
posterior side of the embryo
- Primitive streak forms in the epiblast
- Hypoblast will be displaced anteriorly and form the
germinal placenta
- Germ crescent: will form the PGCs that will
eventually go to the genital ridge
- Primitive streak: like a mountain of cells; will form
a groove: moving cells will form the mesoderm and
endoderm

Mammal (alecithal egg)

Epiblast gives rise to all parts of the organism

All cells that will ingress will form the Hensen’s
node
Order of ingression is very specific:
- capitulates the developmental pattern in the bird
1. pharyngeal cells of foregut
- blastocyst
2. prechordal plate/ head mesoderm
- no yolk: empty space surrounded by cells
3. chordamesoderm that becomes notochord
- ICM: will form little spaces that will coalesce to form
Notochord underlies the neural ectoderm: that’s why
amniotic cavity: amnion
it is last
- the rest of the cells will be like the blastoderm in the
All the rest of the mesoderm and the endoderm will
avian
ingress through the lateral areas of the primitive
- one will form the epiblast; the other hypoblast
streak
- hypoblast will form the yolk sac
- epiblast will form the primitive streak
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- ingression in the primitive streak - mosaic: early on ay nadetermine na ung fate;

- sometimes, two primitive streaks form: creation of cannot change
two identical organisms - regulative: mababago pa; certain window of time
- differentiated by time
MECHANISMS IN GASTRULATION
In amphibians (as studied in Xenopus laevis)
-grey crescent indicates the future dorsal side
- point of entry is the future belly/ ventral side
- the blastopore is the future posterior side usually
marking the anal area
dorsoventral axis: fertilization/sperm entry
anteroposterior axis: point of invagination and
involution
Grey crescent: biomarker to developmental stages
Ventral side: entry of sperm

in birds:
- determination of dorsoventral axis is through the
difference in pH and charge – the + charge in the
subgerminal space due to Na+ and the relatively low
pH induces the ventral side
- side facing the albumen becomes the dorsal side
- anteroposterior axis is determined by the
hypoblast, where it starts to form is the posterior
side
- ingression in birds
- made possible by coating of hyaluronic acid on
the cell surface
- only HNK+ (sulfated glucuronic acid) cells in the
epiblast can ingress
- cells change from the epithelium unto bottle-
shaped cells then into mesenchymal cells
Anteroposterior axis: Delamination of hypoblast
Dorsoventral: difference in pH
- stretching of the chordamesoderm and primitive
streak anteroposteriad is due to convergent
extension caused by cells rapidly dividing,
intercalating and spreading
- chordamesoderm will become the notochord
- chordamesoderm ingress in the hensen’s node
- migrating cells interact with each other through cell
adhesion molecules (CAM):
- cadherins
- CAMs of the immunoglobulin superfamily
- N-CAMs
- integrins
- lectins and selectins
- glycosyltransferases
- cells associate with substance of the extracellular
matrix such as fibronectin, laminin
- cadherins are not permanent structures: mediate
binding of non-junctional complexes
DETERMINATION
- fate of the cells, fully committing itself
- the cell is already starting its program to the
commitment of its fate
- Programming and commitment of the cells to their
fates: due to cell interaction
- Mosaic/determinate (Drosophila, C. elegans) and
indeterminate/regulative (frog): development just
differ in time of determination
Indeterminate or regulative blastomeres: flexibility of
cells; have a certain window of time
Early gastrula: something happens that seals the fate
Presumptive epidermis: transferred into another area:
will not become part of the neural plate but part of
the epidermis
- Determination is a function of turning on of selector
or master genes
- start the cascade of events downstream
- Positional information- used in determination and
differentiation
Some Concepts in Determination
Prospective significance (fate)
- the usual and specific fate of the cell in the course of
normal development and differentiation
- usual if it is allowed to develop normally
Prospective potencies
- all the possible fates of the cell when it is still open to
induction of neighboring cells
- usually restricted upon reaching late gastrula stage
- course of progression of development: becomes
narrower and narrower
THE PRIMARY ORGANIZER
- the dorsal lip of the blastopore
- the first inducer
- the primary inducer which subsequently triggers a
cascade of induction reactions
- this eventually results in the formation of the
embryonic shape
- once neurulation has happened, other events follow

In transplantation experiments, the dorsal lip of the
blastopore (the region fated to give rise to dorsal
mesoderm) not only did not change fate when
transplanted, but induced surrounding host cells to
change their fate.
If we remove a presumptive notochord
(chordamesoderm) and transferred to other side of
embryo: it will organize another dorsal lip
Conjoined twins: because of extra primary organizer
- Rescue of irradiated embryos by the transplantation
of dorsal marginal cells of normal 32-cell embryos.
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- Without such a rescue, irradiated embryos fail to
gastrulate, forming "belly pieces."
- If the dorsal marginal zone cells of a normal embryo
are transplanted into the irradiated embryo, they will
induce the formation of mesoderm and the body
axis, thereby producing a normal tadpole. (After
Gimlich, 1986.)
- irradiate blastopore lip
PROCESS OF PRIMARY INDUCTION
Mesodermalizing/vegetalizing induction
- broad ring of equatorial cells in the blastula specified
to develop mesoderm cells by signals from the
vegetal pole cells
- vegetal pole cells: signal to convert inner marginal
rings to mesodermal cells
- blastocoel plays role in keeping animal pole and
vegetal pole cells apart: so that mesodermal layer
will really come about
Dorsalizing induction
- dorsal side and head tail polarity is specified by
signals from under the cortical layer of the grey
crescent (Nieuwkoop center)
Neural induction
- signals by the Spemann’s organizer and subsequently
by the roof of the archenteron (dorsal mesoderm)
cause the ectoderm to become central nervous
system
Chordamesoderm/ dorsal mesoderm: primary organizer
Lengthening: convergent extension: nagiging notochord
na sia
When the notochord underlies the ectoderm: it will
become the neural plate
“It is not birth, marriage or death but gastrulation that
is truly the most important time of your life”
(Lewis Wolpert, 1986)
MESODERM FORMATION AND NEURULATION
- mesoderm: formation also of brain and spinal cord
Fate mapping
Connect through the fibronectin layers
Vegetal pole: will give rise to endoderm
Mesoderm: marginal layer cells
Dorsal lip
Cellular wave:
cells going
inside are
changing as
they move
Dorsal lip not fixed population of cells, rather its a
"cellular wave" made up of continually changing

population of cells that pass through during
gastrulation.
Niewkoop and Nakamura Expts in the 60s
- "mesoderm fate" does not exist in the early
blastula, but is induced at the equatorial region by
an inductive interaction between the vegetal cells
and animal cells
- mesoderm fate is induced in the marginal area
- interaction of animal and vegetal pole cells
- ectoderm: blue, will form because they will not
receive the signals to become the mesoderm
- signals are from the vegetal pole cells
Combining Expt. of 32 cell stage Frog Blastula
(Dale and Slack)
- cells in between: are also determined to become the
dorsal and ventral mesoderm
- dorsal mesoderm: opposite of sperm entry
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- cells mesodermal in nature: will differentiate into
mesodermal cells (different ung mesodermal cells
formed sa ventral at sa dorsal)
- dorsalmost cells of the vegetal pole, if incubated with
ectoderm: dorsal mesodermal structures: notochord
No ventral mesodermal structure
- The farther away from the dorsal side; the less ang
magegenerate niang dorsal structures
- Dorsal mesoderm: associated with notochord
- Ventral mesoderm: associated with the heart,
cardiovascular
- Lateral: kidneys; etc
More experiments: Dale and Slack
- The dorsal-most vegetal cells had the greatest ability
to induce dorsal mesoderm, while the ventral-most
vegetal cell had the greatest ability to induce ventral
mesoderm.
- Thus, even at very early stage the vegetal cells must
be secreting a "mesoderm inducing" signal.
- they suggested a dorsal to ventral gradientin
dorsal mesoderm inductive ability.
- The dorsal-most vegetal cells that induced dorsal
mesoderm (the primary organizer) was named the
Nieuwkoop Center in honor of the developmental
biologist Nieuwkoop.
Nieuwkoop center: endodermal cells; nanggaling sa
kanila nag signals that will convert the mesoderm cell
above it into dorsal mesoderm
What are the molecular inducers of mesoderm
formation?
From dorsalmost
cells: dorsal
mesoderm cells
N. center: overlap
of the presence of
TGF-β signal and β-
catenin
accumulation
- The dorsal side is distinguished molecularly: presence
of β-catenin
- Ventral side: siamois gene: mesodermalizing gene
Silent: Tcf-3 (silences them)

- Dorsal side: siamois gene
Β-catenin: activate the gene
- Siamois protein: act as transcription factor the will
help produce goosecoid gene
- Goosecoid: believed to be the determinant of
organizer function. There may be some homology
between fly and vertebrate goosecoid function
Properties of organizer tissue
- ability to become dorsal mesoderm
- ability to convert surrounding mesoderm into lateral
mesoderm
- ability to dorsalize the ectoderm into neural ectoderm
- ability to initiate movements of gastrulation
- ability to induce neurulation
β catenin locate at dorsal side to perform its
function
- Glycogen synthase kinase 3: natural inactivator of
β-catenin
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- Disheveled (Dsh) proteins: upstream; inhibitor of
GSK-3
- β-catenin in dorsal side will be observable in function
- During cortical rotation: Dsh undergoes radical
rearrangement; goes to dorsal side
- Inhibition of GSK-3: activation of β-catenin
- why impt? β-catenin is a determinant of dorsal
mesodermal cell: impt because dorsal mesodermal
cells become the chordamesoderm that will become
the primary organizer
- privides conceptual network as to why molecules
goes to the dorsal side??
- In Xenopus, VegT and Vg1 (found in the
endodermal area) act synergistically with β-catenin
to activate a gradient of Xnr proteins across the
endoderm, highest dorsally.
- Xnr proteins: Xenopus nodal related protein;
concentration gradient in the endoderm
Highest Xnr in the dorsal area: overlap of VegT, Vg1
and β-catenin
- Ventral mesoderm expresses BMP4 and Xwnt-8.
- BMP-4: bone morphogenetic protein; found in the
bone first
- Xwnt-8: Xenopus wingless??
- High Xnr represses BMP4 and Xwnt-8 in the
overlying mesodermal cells so that BMP4 and Xwnt-8
are expressed in a ventral to dorsal gradient.
- how is the Xnr activated: synergistic relationship with
β-catenin and VegT and Vg1
Neurulation as induced by chordamesoderm
- very specific order of involution of cells
- chordamesoderm locates itself under the animal pole
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- when they are already underlying the ectoderm,

chordamesoderm will differentiate into the notochord THE PRIMARY ORGANIZER MOLECULES
- now starts to change in shape: becomes cuboidal - first event: neurulation; beginning of the embryo
then columnar - organizer: notochord secrete the neuralizing trio
- will form the neural plate then tube Induction of neurulation
- in between the ectoderm that forms the epidermis - The organizer secretes Noggin, Chordin, Follistatin
and the ectoderm that forms the neural plate is the that bind to BMP4 and prevent BMP4 from binding to
layer of cells that will form the neural crest its receptor.
- mesoderm: form from the margin, formed separately - act as a competitive inhibitor in the dorsal side
- neural crest: also; will have very different fate that’s - This leads to an effective ventral to dorsal gradient of
why formed separately; very mesenchymal BMP4 and Xwnt-8.
- Schwann cells - the true neural fate will ensue
- pigment cells
- parts of the adrenal medulla
- nerves of sympathetic nervous system
- chordamesoderm when it underlies the ectoderm,
transforms by induction
- during gastrulation, cells are placed in new
neighborhoods to interact with each other to interact
in a new way
- chordamesoderm: brings about neurulation

There is a gradient in the BMP4 and Xwnt-8

Dorsal: neural ectoderm
Ventral: epidermal ectoderm
Going to the dorsal: in presence of the trio: BMP4
nagdedecrease ang effect
Because of this, we have different structures arising
Infolding of the neural tube The action of intrinsic factors
Antineuralizing Agents
- Surprisingly, the default fate of ectoderm is neural!
- to become the neural tube; or give rise to neural
cells
- how is it overcome by the ectoderm?
- BMP-4 and Xwnt-8 act as anti-neuralizing agents
and specify ventral mesodermal and endodermal fate
and epidermal ectodermal fate.
- act antagonistically with the molecules coming from
the notochord that will neuralize the ectoderm
- Dorsal endoderm, dorsal mesoderm and neural
ectoderm is the fate of cells NOT exposed to
threshold values of BMP-4 and Xwnt-8.
- bakit di nafefeel ang sa dorsal side? Effects of the
neuralizing agents from the notochord

- ectoderm will have different fates
- neural plate portion overlying the notochord
- anterior: brain
- posterior: spinal chord
- ventral and lateral ectoderm: epidermis
- side where the notochord underlies the ectoderm:
trio will act against the BMP4 and Xwnt-8
- neural plate cells will take on their default fates
- posterior: FGF + RA (from rhomben to spinal chord)
Fibroblast Growth Factor
Retinoic acid
Xnr: causes the appearance of dorsal??
Before the appearance of trio
Notochord will not arise without it
SECONDARY ORGANIZER
- those that are not in the influence of the notochord
kasi nauna sila mag involute; more anterior to the
notochord
- Foregut endoderm and head mesoderm- act as
secondary organizer substances
- promotes the development of the most anterior parts
of the brain
- Frzb competitively binds to Xwnt-8 and prevents
Xwnt-8 signaling. Dickkopf (malaking ulo sa
German) and Cerberus have similar functions
- more active ung Xwnt-8: cannot bind to its receptors
that’s why it will dorsalize the structure
- Thus both BMP-4 and Xwnt-8 are functionally
expressed in a ventral to dorsal gradient.
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- These two signaling molecules specify ventral
mesoderm and endoderm at high concentrations and
intermediate mesoderm and endoderm at low
concentrations.
Kelan nagssimula makita ung notochord?
Causes the differentiation of brain parts
Underlie only a certain parts
Posteriorizing Agents of Neurulation
- Gradients of Wnt. Retinoic acid and eFGF are
found to induce posterior parts of neural tube such
as hindbrain and spinal cord
How all of this molecular structures will shape/organize
the embryo
Wnt and BMP4: inhibited by the inhibitors so that the
anterior parts will develop
Posterior portions: coming from the notochord: Wnt,
FGF and RA gradient to pattern the posterior neural
tube
The Drosophila paradigm: Specification of body
axes
- STUDY
- complexity: three body axes that will develop
- axes: influence development of certain structures
Ex. pattern in antero-posterior axis: no tail in head
Dorsa structures are different from ventral side
- axis of the Drosophila
- principles are also developing in the vertebrate
ANTERIOPOSTERIOR PATTERNING OF XENOPUS
EMBRYO
- creation of dorsal and ventral: sperm entry
- anteroposterior: dependent on homeobox genes
- Hox genes - differentially expressed along the
anterior-posterior axis of the developing animal in a
3'-5' anterior-posterior order along the body.
- Fly and mouse patterning conserved via Hom/Hox
genes
- Morphogen gradients established by the organizer -
directly or indirectly regulate Hox gene expression.
Are upstream
- Retinoic acid gradient - direct regulator of Hox
gene expression.
- Many Hox genes have regulatory domains that
contain RA response elements (RERs).

- Organizer - thought to be the source of RA gradient.
- the patterning is determined by the Hox genes: ex.
why the head is always in the anterior region; why
eyes are not in the pwet region
- The comparison/homology present in the mouse and
Drosophila
- Super layo ng complexity ng dalawa
- Names: indicates the parts of the body of the fly
- Although the mouse will not develop the same
structures, it has the same/homolog Hox genes that
will develop structures that have the same function
as that of its homolog in the fly
- Hox genes: quadruplicated through the years
- Humans: 4 copies
- Structures that will arise in very specific locations in
very specific order
- Not identical; corresponding lang
- Some are not present
- Happen over millions of years, in a particular portion
of the body: paralogous group that will be active
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- In mouse: a1 and b1 active in the brain
- Paralogous group: Have to be present for certain
structures to arise in the certain parts of the body
- Anterior Hox genes are very sensitive to RA for its
activation; gradient in response
- the action of the gene in 3’ to 5’ direction: 3’ most
genes will be expressed in anteriormost parts of the
body
5’ most paralogous groups: expressed in the
posterior
- not only is there a spatial linearity; there is also a
temporal linearity
- first paralagous groups that are expressed are in the
3’ groups
- 3’ groups are expressed first
- anteriorside is most developed
Why? Because of the linearity of exression
- spatial-temporal colinearity
Spatial: anterior to posterior
Temporal: early to late exression
- in the chick/avian, mouse paradigm
- hox genes, types of paralogous groups that will be
expressed determine which type of structures will
arise in the anteroposterior axis
Left/right Axis in Xenopus laevis
Molecular mechanism involves:
- Expression of nodal gene Xnr-1
- Expression of Xnr-1 is dependent on proper
localization (via microtubules) of Vg-1 proteins
- Xnr induces expression of PitX2 gene
- wherever Xnr-1 na very high level: where the Xnr
activates the PitX2 gene
Development of left side
Why impt? Left: where heart is, and spleen
PitX2: left sidedness; determines also the coiling of
the digestive tract (in the counterclockwise manner)
- pag sa right nilagay ung PitX2: randomized nung
coiling of digestive
Lungs, liver: different number of lobes sa left and right
side
RESEARCH!
Axis Determination in the Chick
- dorsoventral axis due to the differences in pH in the
subgerminal space and albumin
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- Anteroposterior axis traced to the rotation of the - Rightsidedness: PitX2 is inactivated

ovum in the hen’s reproductive tract creating - FGF-8: negates Car which cannot anymore inhibit
posterior marginal zone (point where 2ndary BMP
hypoblast forms)
- anteroposterior axis: formation of the secondary
hypoblast
Hypoblast: does not really form a part of the embryo
Posterior marginal zone: created and indicates the
posterior future side of the embryo

The Role of Gravity

Yolk where the blastoderm is: umiikot ikot

Blastodisc becomes skewed to one side
Uppermost: san nahuhulog ung hypoblast
Future posterior side: where primitive streak will form
The beginnings of the primitive streak is always
associated with area opaca: junction bet. Blastodisc
and yolk (marginal area)
PMZ (Avian) equivalent to amphibian Nieuwkoop
center
- Posterior marginal zone
- induces formation of primitive streak
- just an inducer; does not participate in the formation
- When grafted at anterior region of marginal zone:
induces primitive streak and Hensen’s node but did
not contribute to the cells in both
- Where B catenin also seems to localize
Axis determination in Mammals
- Anterior-posterior axis- have 2 signalling centers: the
node and the anterior visceral endoderm; serve
as source of organizing molecules
– Chordin, Noggin from the node
– Hesx1, Lim 1, Ot X-2, and Cerberus from ant
visc endoderm
– dependent on expression of Hox genes
- ung pinaka3’: anterior parts; earliest expressed
Dorsal- ventral axis determination

Hensen’s Node and Derivatives as 1° organizer

- structures that will give rise to the primary organizer
will ingress through the Hensen’s node
Secrete Chordin, Noggin, and Nodal proteins
- no follistatin in avian
- Antagonize BMPs and dorsalize ectoderm
- FGFs needed to inhibit effect of BMP4 (wala sa
amphibian model)

Left and right axis in Avian model

- PitX2: in amphibians
- is determined by the PitX2: left sidedness - future dorsal: will cavitate: that’s where you have the
amnion
- trace it by looking at the primitive streak
- Lefty-1: inhibits the expression of FGF-8 - from epiblast: will form the primitive streak
FGF-8: activates the SNAIL protein: for right - embryonic pole: future dorsal side
sidedness
Left and right axis determination in Mammals
- Nodal and Lefty-2: when activated inihibits Snail
- BMP: inhibits Nodal and Lefty-2 - Nodal and Lefty on left
- Car (Caronte): activated by left side of Hensen’s - Snail on right
node
Shh: sonic hedgehog: starts the activation
Transcription factor that transcribes Car
downstream
Inhibits BMP

SHH: a known long-range signaling molecule, is a
right determinant that functions to repress
expression of left determinants on the right
- Left: SHH; activates nodal
- Right: FGF-8: triggers a series of events that
activates SNR
- In the mouse: the leftsided structures are
determined by PitX2; because of interplay of FGF-8
not SHH
- FGF-8: activates nodal and lefty
- Hensen’s node of mammals: have actively beating
cilia; beat towards the left
- Drive the secretions of H. node to the left
- Right sidedness: the absence of left side molecules
- Bar: molecular bar; prevents the entry of left sided
molecules towards the right
- SHH: prevents the empty from left towards the right
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THE ECTODERMAL DERIVATIVES
Fate of the Ectoderm
- germ layer that covers the whole embryo
- gives rise to very disparate structures
- why anterior pituitary lang? where does
neurohypophysis comes from neural ectoderm:
ventral portion of the diencephalon
Adenohypophysis: Rathke’s pouch
- How about the sensory neurons? Come from neural
crest: ganglia: aggregations of nerve cell bodies
outside the CNS
San pumupunta ung fibers nia: sa nerve cells
Sensory ganglia + axons or fibers = PNS
Primary neurulation
- formation of anterior neural tube
- mechanism is common among vertebrates
- neurulation is brought about by the induction coming
from the chordamesoderm
- sinking in to form the neural tube
Secondary neurulation
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- formation of posterior part of neural tube

- differ among vertebrates

Secondary neurulation in the caudal region of a 25-

somite chick embryo. (A) The medullary cord forming
at the most caudal end of the chick tailbud. (B) The
medullary cord at a slightly more anterior position in
the tailbud. (C) The neural tube is cavitating and the
notochord forming. (D) The lumens coalesce to form
the central canal of the neural tube.

After the anterior neural tube is formed, mesenchymal

cells form a rod that continues to the end
Will form the posterior portions of the neural tube

Development of neural tube

- gradual closure in a anteroposterior zipping up
- dorsoventral patterning

- widened end: brain

- anterior portion na bukas pa: anterior neuropore
Posterior na open: sinus rhomboidalis

most common neural tube defect in the United States -

affecting 1,500 to 2,000 of the more than 4 million
babies born in the country each year

Factors affecting dev of nervous system:

- Alcohol (FAS): fetal alcohol syndrome
- Tobacco
- Medications and street drugs
- Household toxins (pesticides)
Pre-natal medicine: folic acid: helps in the proper
closure of the neural tube of the child
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Spina bifida: di nagclose pero di masyado bad

Anencephaly: improper closure tlga

Shh
Dorsal-ventral patterning of the spinal cord

BMP in dorsal; Shh in ventral

- neural tube that will become the spinal cord

- green: notchord
- ectoderm and notochord will act on the neural tube
and will pattern the neural tube
- influence of the epidermis
sensory neurons (dorsal side): nasa sensory ganglia!
Outside the CNS
Ventral: motor neurons: soma (cell body) The notochord already expresses Shh to pattern the
Sends signals in the form of BMPs: roof plate takes future ventral side
on the same signal BMPs from epidermal ectoderm
- from the notochord: SHH Interaction of SHH and BMP causes the appearance of
Antagonistic function: those exposed with BMP will molecules in marginal area: Slug: defines the neural
form different structures crest cells
Gradient!
Different structures arise because of the extrinsic Anterior-posterior patterning of spinal cord
factors: BMP in dorsal
Motor neurons: will arise only in ventral because of
Shh
Interneurons: connect the motor to the sensory
neurons
Cross section of spinal cord
 15

- inner portions: H configuration

Made up of neurons, cell bodies, neuroglia
- white matter: made up of fibers
- ventral area: motor function
Base of H: motor neuroblast: will give rise to
motor neurons
Bipolar appearance: will become unipolar, retracts
from the lumen of neural tube
Will then become a multipolar neuron: formation of
dendrites
- Spinal ganglia: sensory
- motor nuclei: aggregation of cell bodies inside the
CNS
- from ganglion: towards CNS if sensory
- in motor nuclei
From cell body of motor: towards the axons of the
spinal nerve
- spinal nerve: motor and sensory component
- Hox genes Carries dendritic function: from the cell body to the
- 3’-5’ expression axon
- expression of genes in paralogous groups Breaks up into two
- dorsal ramus: innervate dorsal musculature, skin
Histogenesis of the spinal cord - ventral ramus: innervate ventral portions
- ramus communicans
Part of PNS? Yes
How do they differ? Will go to sympathetic ganglia
Function: innervates the visceral areas of the body
Visceral: stomach, intestines, liver
Rcvs messages to send the signals to the post
ganglionic fibers (wrt to sympathetic ganglia)

- pseudostratified epithelium: anchored to a basal

lamina
- mabilis magmitosis to give rise to the neurons and
interneurons arising from them
- depending on the cell cycle is the location of the
nucleus?
G2 and M
Anaphase, telophase…: lumen place Telencephalon: cerebrum
Appear in different layers: but it is only the nucleus - gives rise to the two hemispheres
that’s relocated depending on the stages of the cell - cerebrum: all the motor functions in the body begin
cycle with this then fine tuned in the cerebellum
- mitosis: canal/lumen
Diencephalon
- roof: gives rise to epiphysis that gives rise to the ___
- main body: thalamus
- like an atrium that you find all switches to connect
to the cerebrum and the other parts of the body
- Integration of impulses to the brain
- ventral portion: hypothalamus
- outgrowth of ventral portion: infundibulum (in adult
will become the neurohypophysis)
Adult xs of Spinal cord
- neuroepithelium is reduced to ependyma cells around
the central canal
 16

Pituitary
- in embryonic: hypophysis
- neurohypophysis: from infundibulum
- adenohypophysis: Rathke’s pocket
- together: pituitary
- hypothalamic-pituitary-gonadal axis

Mesencephalon
- big leap in evolution
- in frogs: center of integration for sense of sight
- in higher mammals: not in mesencephalon anymore
but in the cerebrum (visceral cortex in the occipital
lobe)
- takes on a subdued function
- corpora quadrigemina: superior and inferior
folliculi
Integration of reflexes associated with sight and
Magkakaroon ng iba ibang layers!
hearing
Neurons that will stop nearest to the neuroepithelium
- reduced to integration of reflexes from sight and
forms the first layer
hearing
Granular layer
Purkinje layer
Metencephalon: cerebellum
Marginal layer
- coordinates and fine tunes muscle movements
External Granular layer
Myelencephalon: medulla oblongata
- visceral functions: swallowing; breathing
- motor nuclei

DEVELOPMENT OF THE BRAIN

- Interchange in the placement of white and gray
matter
Gray matter: sa labas
- spinal: gray matter sa loob; white sa labas
- Formation of the different neuronal layer from
ventricle to outer layers
- layerings!
- what is the evolutionary relevance of such
arrangement? For efficiency of transfer of signals
from the
Morphology of the outside of the brain: term!!
Increases surface area: a lot more neurons that can
be accommodated to interact with each other

Fate of different embryonic brain parts

- Telencephalon
- Diencephalon
- Mesencephalon
- Metencephalon
- Myelencephalon

Layers
- starting off from the central canal
- migrate outward away from the lumen
- travel through the neural monorail: processes of the
radial glial cells
- migrating neurons and settles in an area
 17

Lateral Inhibition
- kung ang isang stem cell ay nakaabot sa part na
dalawa na lang ang kaya niang igive rise
- the direction to one side is inhibited by signals
- in favor to just one side, towards one side
- proneural genes: will release inhibitory signals to the
gliogenic signals
- gliogenic signals will also secrete inhibitory signal to
the proneural genes (later)

Fate of the neuroepithelium:

Neurons first and then neuroglia
- come from one multipotential stem cell
Along the way, reduction of its stemcellness NEURONAL DEVELOPMENT
- two types of cells - sends out microspikes at the end
- neurons: carry impulses - green: stained for actin (actin for extension)
- neuroglia: supporting tissues - red: microtubules
- oligodendrocytes : equivalent of the functions - microspikes: taste and feel the envi
of the Schwann cells in the CNS; provide If the envi is hospitable, they will settle there
insulation (myelin sheath) - how do they know where they go? Their envi gives
- Astrocytes: give rise to the radial glial cells: them cues
glial monorail; physically supports the neurons - many also die off because they do not receive
Schwann cells enough stimulus
- Microglia: equivalent to the macrophages or
Kaupffer cells in liver
For defense
- others: to line the cental canal and produce the
cerebrospinal fluid

Developing neurons ‘feel’ their way through sensitive
microspikes as they travel to the proper destinations
guided by cues from the environment.
Interaction between the target organ and
growing nerves
- Axonal guidance
- Axonal transport and regeneration
- axons are guided by the substances in the envi
- provided by nerve growth factors
- Results of ablation experiments
- shows how impt the interaction is
- tinggalan ng limb bud: liliit ung nerves kc walang
magsesecrete ng stimulus
- maglagay ng extra: grew more ung sensory neurons
DEVELOPMENT OF THE PERIPHERAL NERVOUS
SYSTEM
- Spinal nerves
- Cranial nerves
The autonomic nerves
- ramus communicans: made up of autonomic nerves
- parasympathetic: emanate from the cranio-sacral
- sympathetic: thoraco-lumbar outflow
- ganglionic chain
18
- axonic ends will synapse with dendrites of soma of
sympathetic ganglia cells
- lahat ng motor neurons that will power the visceral
organs start off at the CNS
There is a fiber that comes out of CNS and connects
with the ganglion
Fibers that get out of ventral root: then ramus
communicans to sympathetic ganglion
Send out post ganglionic fibers: innervate directly to
the organ to be innervated
- parasympathetic ganglion: very long pre-ganglion
that sits right smack of the organs to be innervate
No sympathetic ganglion chain
Very short post ganglionic fibers
- sympathetic: stressful condition
Mediated by release of molecules such as adrenaline
Fight or flight situations
- parasympathetic: daily life
The Cranial nerves
Nerves V,VII, VIII, IX,X- neurons have mixed
source:
- ectodermal placodes and neural crest cells
- ganglionic: sensory in nature; thickened areas
ectodermal in origin
- ectodermal placodes: epidermal thickenings
- after they thicken, they will sink in and participate in
formaton of structures
- olfactory, auditory placode, lens placode
Whole mount of pig
Olfactory (I)
- sensory
 19

- nerve cell bodies not found in brain; found in

olfactory epithelium
Innervates the olfactory epithelium
- sends impulse towards the brain

Optic (II)
- sensory
- nerve cell bodies found in the retina (inner portion of
optic cup previously)
- sends its fibers in the visual cortex in the occipital
lobe of cerebrum
- optic chiasma: ventral portion of diencephalon

Oculomotor (III)
- motor nerve
Cell bodies: found in mesencephalon (ventrolateral
wall)

Trochlear (IV)
- motor
- cell bodies in mesencephalon (goes up and crosses
the isthmus

Trigeminal (V)
- three branches: maxillary, mandibular, ophthalmic

Abducens (VI)
- motor
- cell bodies found in myelencephalon
- fibers go to external rectus of eye

In spinal nerves: ventral root unites with motor root

always to form one unit
Cranial nerves: don’t unite; goes to brain separately

DEVELOPMENT OF THE SENSE ORGANS: THE EYES

The eyes: ideal paradigm to observe serial induction
reaction in development
- very complex organ
- ideal model in observing serial induction
- a certain structures is induced and when it is
formed; it will induce the formation of another
structure
- if the first one will not form; the others will not
form
- first that should form: diencephalon
- how does the dien form?? RESEARCH
- bulges out to give rise to optic vesicle: the
primordium of eye
- induces overlying epidermis to form a placode; the
lens placode that will thicken and sinks in
- optic vesicle will form a cup
- lens vesicle separates from the………….
- lens cover the overlying structures; structures
around it will change to become very thin and
transparent
- mesenchymal structure will be lost and form the
anterior space
- form a down growth and upgrowth to form lower
and upper lids
 20

- it has differentiated into lens fibers (longitudinal);

posterior
- cuboidal cells: anterior

- vesicle: anterior and posterior areas

- anterior: source of all the cells that will give rise to
the posterior parts
Development of the retina - areas will be pushed towards one area
- equatorial part: when it reaches this, it is now
ready to form lens fibers

- neuroepithelum: outer neuroblastic layer: faces - posterior cells: starts to become glassy in
the pigmented epithelium appearance
- inner neuroblastic layer: faces the vitreous humor - secrete crystallin protein
Development of neurons involved in photoreception - first lens fibers to form are in the equatorial area
and seeing - lens: focuses the light that passes throught the
Will arise cell bodies of the optic nerve vitreous chamber to the retina
Will then go to optic stalk then to visual cortex - retina: inner portion
- intermediary cells: horizontal, amacrine, bipolar - pigmented epithelium: outer prtion; epidermal
Connects to photoreceptors on top of epithelium
All these cells are insensitive to light
- rods and cones: sits atop the pigmented epithelium
Photosensitive
Stimulated in such a way that will fire up
Impulse will be transmitted to intermediary cells
Interconnect until they depolarize the ganglionic cells
of the optic nerve
- when light enter the lens, passes the vitreous
chamber, hits the retina
- passing through the optic stalk are ganglionic fibers
Genetics in eye development
Development of the lens Role of Shh and Pax 6 genes
- Pax 6: determines the eye formation
Area where eyes will form
Whole anterior portion: eye field
- in presence of Shh: expresses in anteriormost
portion, Pax 6 will split eye field into two

DEVELOPMENT OF THE EAR: THE ADULT EAR

 21

- neural crest; placodes?? Ano un?

- otocyst form with neuroblast
- neural crest cells are growing right beside it
- enlarge to give rise to 3 semicircular canals (anterior,
posterior, lateral)
- balance: endolymphatic duct (dorsal parts)
- ventral parts: for hearing (cochlea)

- derivative of epidermal placode: inner ear

- outer ear: auricle; external acoustic meatus
- middle: tympanic membrane, tympanic cavity that
houses audtry ossicles
- inner: semicircular canal, cochlea

- organ of Corti: in cochlear canal

- scala tympani
- scala vestibule
- all three are filled with endolymph
- when sound enters the tympanic membrane, causes
th vibration of oval and round window
- auditory ossicles: will vibrate
- placode forms at the induction of rhombencelphalon
- vibration is transferred through the wave-like motion
- thicken and form the placode to form otocyst
in the endolymph…………………………
- that will sink in to form middle ear with the first
- organ of corti: has hair cells
visceral pouch (pharyngeal evagination)
- hair cells: are connected to ganglionic fibers
- outer ear: ectodermal invagination; form with
- temporal lobe of cerebrum
- where they will meet: tympanic membrane
- external auditory meatus will induce formation of
auricle

The inner ear and its nerve supply

- ganglion gves rise to two branches: to organ of

hearing (acoustic ganglion) , to organ of
balance (spiral ganglion)
- come from neuroblast: ganglion 8
 22

DEVELOPMENT OF THE SKIN

- in the beginning: one layer
- upper: periderm: slought off
- basal layer starts to divide: spinous layer on top then
will become a granular layer when it accumulates
proteins specific to skin
- keratin
- statum cornea: when it is filled up with keratin

Needs the ff factors:

TGF-a from epidermis
Transforming growth factor Formation of the Hair
From basal later - formation of epidermal placode
For proliferation of cells - does not form withut the induction of underlying
Autocrine: sila prduce, sila din nakikinabang mesoderm/mesenchyme
keratinocyte growth factor from fibroblasts - mesoderm will form condensation
San kaya fibroblast? X; fibroblasts are cells of the - mesenchyme will form hair follicle
connected tissue - w/o mesoderm: hair will not form
Regulate the proliferation of cells - hair follicle: keeps on growing til it forms hair shaft
Act against TGF-a - hair shaft: contains dead stratum corneum
- outgrowths in hair bulb:
75%of dust in houses are from dead skin cells slought sebaceous glands: secrete oil
off pleuripotent stem cells
8 weeks: from basal layer to stratum corneum: stay
there for 2 weeks
Soriasis: very short time; natatanggal agad

Hair is an epidermal derivative


STUDY THAT!
DEVELOPMENT OF THE MAMMARY GLANDS
- take on different configuration depending on sex
- both male and female start of with milk ridges
- from the axillary to inguinal line: may milk ridges
- axillary portion na lang natitira sa tao
- ruminants: inguinal area na lang
Normal female tissue
- epidermis forming the duct: because of the presence
of specific dermis
- considerably more branched as you reach puberty
With testosterone
23
- cause regression of ingrowth and branching
- at right window of time: will have male phenotype
Without testosterone
- female phenotype
Effects of hormones on mammary gland
development and function
- during puberty: mesoderm underlying the fat pads
will induce more branching
- during pregnancy: branches grows more extensive
Because they will start secreting milk
Presence of lactogenic hormones: prolactin:
promotes secretion of milk in alveoli area
Baby suckling the breast: increase milk production
Oxytocin: massive contraction of myoepithelial cells
surrounding the breast
Negative feedback: on hypothalamus not to secrete
luteneizing hormone which prevents ovulation
Underlying principles of epidermal structure
derivations
- epitheliomesenchymal interaction!
Examples of epidermis and dermis interaction in
chick or mouse
The experiments on TFM tissues
1. Normal ectoderm +TFM mesoderm with
testosterone=female phenotype
2. TFM ectoderm +normal mesoderm=male phenotype
 24

How about the dermis? Where does it come

from?
- Dermatome
- Somitomeres
- Neural crest
- Lateral plate mesoderm

The Neural Crest Cells and their Derivatives

The Neural Crest Cells (Gilbert, 2000)

- Cranial
- Trunk
- Vagal and sacral
- Cardiac

Specification of neural crest cells

Involvement of Slug and Rho

Cranial neural crest from the rhombomeres

 25

Neural Crest Cell determination

What is CATCH-22?
C-cardiac defect
A-abnormalities in the face
T-thymic hypoplasia
C- cleft palate, immune
deficiency (parathyroid defects)
H- hypocalcemia
Deletions in chromosome 22
- Mostly undetermined in premigratory stage- fate is
determined by the environment the cells are
migrating upon and where they will finally locate
- Cardiac neural crest cells determined at premigratory
state
Regulatory Molecules
- Stimulatory: fibronectin, laminin
- Inhibitory: ephrin (e.g. found in posterior
sclerotome)

Trunk n. crest
- Dorsal migration
- Ventromedial migration

Cardiac n. crest
- Migrate to pharyngeal arch 3,4,6
- Become parts of the heart
- Very early determination

Vagal and sacral n. crest

- Parasympathetic enteric ganglia

The autonomic nerves