OCULAR EMBRYOLOGY

Presenter:- Dr Aschalew Mulugeta ( R1 )

Moderators:
- Dr. Social B. ( R3 )
- Dr. Alemnew D. (Ophthalmologist, Oculoplasty sub specialist)
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 OUTLINES
• INTRODUCTION
• GENETICS

• EMBRYOGENESIS
• ORGANOGENESIS

• CONGENITAL ANOMALIES
• REFERENCES

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 INTRODUCTION
• Embryogenesis can be thought of as a series of steps that build on one
another; each step creates a ripple effect on all subsequent steps

• These steps are regulated by genetic programs that are activated in specific
cell types and in a specific order

• Three elements making important contributions to the genesis of eye:

Neural crest cells, growth factors, homeobox genes

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 Homeobox Gene (HOX)
• The blueprint for embryonic program involves the HOX

• Named because they contain a distinctive & highly conserved segment of DNA

 ≈ 180 base pairs long & encodes 60–aa sequence constituting the
homeodomain (provides protein with specific DNA-binding capabilities)

• The HOX genes (master regulators) are expressed before formation of neural
tube & regulate expression of downstream genes

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• PAX6, master gene/switch for eye development regulates differentiation of eye
 Mutation or ectopic expression leads to ectopic eyes, anophthalmia, microphthalmia,
aniridia, Peters anomaly, coloboma, & congenital glaucoma

• SHH gene, secreted by prechordal plate, inhibits expression of PAX6 &

upregulates PAX2

 Responsible for division of eye field into 2 eye globes

 Defect leads to holoprosencephally (Cyclopean eye called synophthalmia)

• PAX2 regulates optic stalk differentiation

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 General Embryology

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 Gastrulation
• Is the process of formation of mesodermal germ layer on day 20

• Exposure to teratogens like ethanol or retinoic acid during 3rd wk causes

primary damage to forebrain neural ectoderm

• This results in a spectrum of malformations including microphthalmia,

anterior segment dysgenesis (Peters' anomaly), iris & ON colobomas, & PHPV

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 Neurulation

• Neural plate: formed by thickening on

ectoderm; later called neuro ectoderm

• Neural groove: central depression on

neural plate

• Neural fold: thickened sides of neural

plate

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 Eye Development

• Develops from 2 germ layers, ectoderm

(Most) & mesoderm

• Commences around day 22 when embryo

has 8 pairs of somites & 2mm in length

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• At ≈ 25 days of GA, 2 optic pits derived
from NE develop on either side of midline,
from diencephalon, eventually form optic
vesicles

• Once optic vesicle touches inner aspect of

surface ectoderm, the vesicle & stalk
invaginates to form a bilayered optic cup

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• As optic cup forms, 2 processes take place:

• First, surface ectoderm begins invagination to

form the lens

• Second, area b/n cup & SE fills with a combination

of mesodermal & neural crest–derived cells that
will form much of the anterior segment of eye

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• Interactions b/n migrating neural crest &
associated mesoderm is essential for normal
crest differentiation

• Many congenital malformations of the anterior

segment probably arise from derangements in
axial migration of ocular neural crest

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• The margins of optic cup grow over the upper & lateral
sides of lens but not over its inferior part

• This inferior area of shallowness or fissure called

choroidal/optic fissure

• Hyaloid vessels pass through this fissure

• It closes at 7th week, leading to closure of optic cup;

failure of closure leads to COLOBOMA

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 Development of the Lens

• At 27 days of gestation, ectoderm cells

become columnar & thickened to form lens
placode

• The lens pit appears at 29 days of gestation

as an indentation (infolding) of lens placode

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• Lens pit continues invagination & form a single layer of
cuboidal cells, lens vesicle

• At 33 days of gestation, cells connecting lens pit to

surface ectoderm degenerates by apoptosis

• Then lens vesicle separates from the surface

ectoderm (future corneal epithelium)

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 Primary Lens Fibers and Embryonic Nucleus

• Between 33 & 35 days, cells of posterior lens vesicle stop

dividing & begin to elongate to fill its lumen

• The elongated cells are called the primary lens fibers which
make up embryonic nucleus

• The cells of anterior lens vesicle give rise to lens epithelium,

a monolayer of cuboidal cells

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 Secondary Lens Fibers

• After they proliferate, epithelial cells near equator

elongate to form secondary lens fibers

• As each fiber cell detaches from capsule, it loses its

nucleus & membrane-bound organelles

• Secondary lens fibers formed between 2 & 8 months

make up fetal nucleus

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 Lens Sutures and Fetal Nucleus

• As lens fibers grow, their ends meet and

interdigitate to form a pattern known as Suture

• Recognizable at ≈ 8 weeks of gestation

• Erect Y-suture appears anteriorly & an inverted

Y-suture posteriorly

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 Tunica Vasculosa Lentis
• Around 1 month of gestation, hyaloid artery branches to form a network of
capillaries, tunica vasculosa lentis, on posterior surface of lens capsule

• They anastomose with a 2nd network of capillaries, anterior pupillary

membrane, which covers anterior surface of lens

• At ≈ 9 weeks, this capillary network is fully developed & disappears shortly

before birth

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 Components of the tunica vasculosa lentis

 Remnant, persists as a small opacity or

strand, Mittendorf dot

 Failure to regress leads to pupillary

membranes, or PHPV (PFV)

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 CORNEA
• At 4–5 wks, surface ectodermal cells
cover the defect left by lens vesicle
invagination

• Then become primitive, undifferentiated

corneal epithelium, composed two cell
layers

• This is followed by 3 successive waves of

migration of neural crest– derived cells

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• At 5th weeks, first wave of mesenchymal cells gives rise to primitive
endothelium
• At 7 wks, 3rd wave of cells migrates into the space b/n endothelium &
epithelium to give rise to keratocytes of corneal stroma

• By 3rd months, all corneal components except

Bowman's membrane are present, corneal nerves
invade stroma, & penetrate through BM to epithelium

• At 7 months cornea has its adult structure

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 Transparency
• The early embryonic & fetal cornea is translucent rather than transparent
b/c more hydrated than in adult

• At about the time that most anterior stromal lamellae

are formed, corneal transparency reaches adult quality

• Failure of keratocytes to produce collagen fibers in lamellar array leads to

scleralisation of corea... Sclerocornea

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 SCLERA

• Neural-crest-derived, except small temporal portion (mesoderm)

• By 6.5 wk, it forms first anteriorly by mesenchymal condensation at limbus

near the future insertion of rectus muscles

• Proceeds in an anterior-to-posterior & inside-to outside fashion

• RPE &/ or choroid is directly responsible for embryonic scleral development

 If RPE or choroid absent-- sclera does not develop (e.g. chorioretinal colobomas)
 If not in contact with choroid - sclera will not grow

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• Anterior sclera fully differentiates by 7th wk, equatorial by 8th wk, & posterior
sclera including lamina cribrosa by 11 to 12 wks’

• At 4 months, scleral spur appears as circularly oriented fibers

• At 5 months, SS is visible behind AC & sclera is well differentiated all around eye

• At birth sclera is relatively thin, highly distensible & translucent (shows blue
color)
• Increased IOP resulting in a buphthalmic eye during the first 3 years is b/s it
loses some of its high distensibility

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 Anterior chamber , AC angle , and TM formation

• AC is first recognized as slit like space b/n the developing corneal endothelium
& iris epithelium
• PC develops as a split in the mesenchyme posterior to iris & anterior to lens

• AC & PC communicate when PM disappears & pupil

is formed

• In 7th week – angle of AC is occupied by mesenchymal

cells of neural crest origin- forms trabecular meshwork

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• By 3rd month angle recess deepens & forms iridocorneal angle

• Schlemm canal develops by end of 3rd month from channels derived from
mesodermal mesenchyme
• Uveoscleral outflow tract forms at 4th month

• In the final wk GA, TM undergoes fenestration &

communicates with AC

• AC angle continuous to recede until 6-12 month after

birth when it become adult type appearance
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 IRIS
• Mesenchyme migrating into space b/n lens epithelium & corneal endothelium
becomes pupillary membrane during 8th wk

• Three structures (PE, NPE & PM) ultimately fuses

to become an iris

• The dilator muscles are a direct extension of

anterior iris epithelium

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• The pupillary sphincter & dilator smooth muscles represent the only
muscles in the body of neural ectodermal origin

• Pigmentation of posterior epithelial cell begins at pupillary margin at

midterm, by 7th month iris is fully pigmented

• Pigmentation does not occur in anterior epithelial layer of iris

• Stromal collagen formation is enhanced during the ninth month

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• Pupillary membrane begins to degenerate at ≈ 6-7th months of GA through
apoptosis & phagocytosis by macrophages

• Opening in the central part of iris forms pupil

• Iris stroma & dilator muscle, still immature at birth - pupil appears miotic

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 CILIARY BODY
• At 10 wk mesenchymal cells get condensed at its anterior surface to form the
stroma of CB
• By 12 wks, mesodermal proliferation leads to infolding of neuroectoderm
which give rise to 70-75 ciliary processes

• Ciliary processes are lined by 2 layers of

epithelium, both from NE

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• At 12 wks, there is myofillament proliferation which forms smooth muscles of
CB by 5th month
• Ciliary muscle continues to develop for at least 1 year after birth

• During 4th month, long ciliary arteries have formed the major arterial circle

• Unlike those of ciliary processes, muscle capillaries are not fenestrated

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 CHOROID

• Mainly derived from inner vascular layer of mesenchyme that surrounds

optic cup

• Layer of fenestrated small blood vessels, choriocapillaris, forms first

(2ndmonth) followed by development of outer layer of larger vessels

• During 3rd month, a middle layer of arterioles forms b/n them

• NCC - derived melanocytes in the choroid develop later in gestation

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 Retina
• Develops from the two parts of optic cup

• The apposed surfaces of the 2 layers are ciliated

 The inner-layer cilia forms photoreceptors,
while outer-layer cilia regress by 7th wk

• Development occurs concentrically, beginning in

the center of optic cup & extending peripherally,
posterior to anterior except for macula

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 Neurosensory retina
• Development is driven by overlapping cascades of genetic programs

• Lamination of NSR retina occurs at ≈ 8–12 wks with formation of inner (7th wk)
& outer neuroblastic layers, & completes at 4½ months

• Retinal differentiation commences when mitosis has practically stopped

• Ganglion cells appear to be the first to differentiate almost simultaneously
with Müller's cells

• Internal & ELMs form when cells cease to proliferate & begin to differentiate

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 Development of the neural retina

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 Macular Development

• Differentiation of macula commences relatively late

• The earliest evidence of maculogenesis is localized increase of superimposed

nuclei in the GCL during 5th month

• The synaptic contact established among photoreceptors, BPCs, & GCs b/n 10th to
15th wks is maintained

• Layer of Chievitz persists until after birth, in macular region

• Large accumulation of cells in ganglion & INL of the parafoveal area are
characteristic of mature macula
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 Retinal vasculature
• Develops from remnants of hyaloid artery which bud of by 4th
month to form CRA
• Branches of HA supplies developing lens, ON, vitreous

• Hyaloid artery system atrophy & regresses in 3rd trimester

• Nasal retina completes vascularization prior to temporal retina

• By 8thmonth all retinal part are vascularized except for portion of

peripheral temporal retina which completes 3 months after birth

• This is the basis for zones I–III in the classification of ROP

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 Optic nerve formation
• Develops at 24 days from neuro-ectodermal cells-derived
optic stalk, surrounded by NCCs

• Surrounding NCCs form meninges, which form ON sheath by 4th month

• NECs form surrounding oligodendrocytes

• At 6th wk of GA, NECs begin to vacuolate & degenerate, providing space for
migration of RGC axons (at 7th-8th wk occupy optic stalk & reach the brain)

• Myelination starts near chiasm ≈ 7th month, progresses distally & stops at
lamina cribrosa ≈ 1 month postpartum
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 Vitreous and Hyaloid system
Primary vitreous:
• The earliest vitreous, mostly consists of hyaloid vasculature with some
associated matrix & NCC components

• Vascular endothelia are of mesodermal origin

• The hyaloid vasculature reaches its greatest development at ≈ 9 wks

• During the 4th month, hyaloid vessels & its branches atrophies progressively

• Composed of fibrils, & as it regresses, it is surrounded by secondary vitreous

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 Secondary (Definitive) Vitreous
• Forms from hyalocytes as primary vitreous regresses
• Occurs during 7th to 8th wks, after closure of optic fissure

• Consists of type II collagen fibrils

• It is avascular gel like substances occupying the space b/n
primary vitreous & retina

• Remnants of PV include the hyaloid canal which remain throughout life as

Cloquet canal, and its anterior extension, hyaloideocapsular ligament (aka,
ligament of Weiger)

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 Tertiary Vitreous

• Originate from collagen fibrils synthesized

by nonpigmented ciliary epithelium

• Between months 4 & 6, zonular fibers of

lens develop from tertiary vitreous with
mostly mesodermal & ectodermal
contributions

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 EYELIDS

• Upper eyelid develops at 4–5 weeks of gestation from surface ectoderm in

region of future outer canthus (frontonasal or paranasal processes)

• At 7th wk, both upper & lower eyelids become discernible as undifferentiated
skinfolds that contain mesoderm which would form muscles of lid & tarsal
plate

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• At 8th to 10th wk, margins of folds fuse by desmosomes (starting nasally)
• Followed by development of cilia & gland (3 to 4 months')

• Orbicularis muscle condenses in week 12, after fold fusion

• Eyelid adhesions break down by 5-6 month; coincident with secretion of sebum
from sebaceous glands

• Eyelid differentiation at 7th month

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 Lacrimal Apparatus
• Multiple solid ectodermal buds of epithelial cells proliferate from basal cell layer of
conjunctiva in anterior superotemporal region of fornix

• Lacrimal gland begins to develop b/n 6th & 7th weeks

• At 3 months, ducts of LG form by vacuolation of cord cells & development of lumina

• Full development of LG is reached by 3 to 4 years post natally

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• Lacrimal glands are small & do not function fully until ≈ 6 weeks after birth

• The lacrimal drainage apparatus also is of ectodermal origin, surrounded by

muscle of mesodermal origin

• Lacrimal puncta open after separation of the eyelids

• Canalization begins 4th month

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 Bony Orbit

• At 4 wk of gestation, frontonasal & maxillary processes of NCCs occupy space

surrounding optic cups
• NCCs give, bones, tendons, cartilage, fat, & connective tissues of orbit

• All bones of orbit are membranous except lesser wing sphenoid, which is
initially cartilaginous

• Ossification begins in 3rd month, & fusion occurs b/n 6th & 7th months
• Air sinuses develop mainly postnasally

• Eyeball reaches adult size by 3 years, but orbit attained as late as 16 years
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 Extraocular Muscles
• EOMs form from paraxial & prechordal mesoderm, differentiate 1st at their
insertions, later at their origins

• Interactions among optic cup, mesoderm, & NCCs are crucial to proper
development & organization of EOMs

• If optic cup fails to form & eye vesicle turns into a cyst (microphthalmia
spectrum), EOMs often develop anomalously

• Congenital cranial dysinnervation syndromes involving EOMs: Duane retraction

syndrome, Marcus Gunn jaw-winking, Möbius, & congenital fibrosis of EOMs
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 Developmental Anomalies

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 Cryptophthalmos

• Hidden eye
• AR/AD
• Failure of development of conjunctiva, eyelid, brows, &
lashes (ablepharon)

• Cornea is merged with epidermis

• AC, iris, & lens are variably formed or are absent

• May be unilateral or bilateral, or complete or partial

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 Anophthalmos
• True anophthalmia: total absence of tissues of the eye ( SOX2 gene defect)
• It is rare & associated with lethal mutations

 Primary anophthalmos, usually bilateral, occurs when

primary optic vesicle fails to grow out from cerebral vesicle at the 2-mm stage

 Secondary anophthalmos, results from anomalous development of anterior neural

tube
 Consecutive anophthalmos, caused by secondary degeneration of optic vesicle
after it has been formed

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 Microphthalmos
• Small eye with AL at least 2 SD below normal AL/age (<15 mm at birth, <19 mm
for 1 year, <21 mm for adults )

• All children with microphthalmia have hypoplastic orbits

 Simple/ Nanophthalmos, relatively normal eye but structurally small
• Hyperopia, macular hypoplasia, thick sclera
• Shallow AC, risk of closed-angle glaucoma

 Complex (microphthalmos with orbital Cyst), results from failure of choroidal fissure to
close
• Mutaton of CHX10
• Associated with microcornea, sclerocornea, COs, aniridia, Peters anomaly & cataract
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 Synophthalmos/ Cyclopia

• A single eye or an apparent midline fusion of 2 eyes in

upper, median portion of face

• Mutation of SHH
• Associated with holoprosencephaly

• Two embryologic mechanism

 Bilobed ectodermal tissue or previously separated
globes

• Many fetuses have chromosomal abnormalities & are

spontaneously aborted
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 Corneal anomalies
Microcornea
•Corneal diameter less than 9mm/10mm
•Arrest of corneal growth in 5th month or related to overgrowth of
anterior tips of optic cup which leaves less space for cornea to develop
•Inherits as AD/AR trait

Megalocornea
•Corneal diameter more than 12mm at birth or 13mm after 2 years

•Associated with abnormal collagen production-Marfan syndrome

•Inherits as X-linked recessive pattern
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 Persistent Hyperplastic Primary Vitreous/ PFV
• Occurs due to failure of hyaloid & tunica vasculosa lentis to regress

• May be anterior or posterior PHPV

• About 90% unilateral

• Clear or cataractous lens

• Fibrovascular plaque
• Iridohyaloidal vessels

• Microphthalmia
• Angle closure glaucoma
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 Anomalies of the Retina

• Retinopathy of prematurity

• Normally, vascularization occurs in low O2 tension in utero

• Premature baby has incomplete vascularization of retina

• Hyperoxia ( O2 supplement) causes vasoconstriction, leads

to ischemia which triggers neovascularization

• Other retinal vascular anomalies: Coats disease, Von

Hippel-Lindau disease, Familial exudative
Vitreoretinopathy

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 Coloboma
• Retinochoroidal coloboma
 Defective closure of embryonic fissure, observed inferonasaly
 AD disorder, may be associated with other anomalies
e.g. Microcornea, RRD, CHARGE

• Eye lid coloboma

 Failure of mesodermal folds of lids to meet or from premature
separation of the lids
 Partial or full-thickness defect
 Associated with cleft palate, mandibulofacial dysostosis, limbal
dermoids, lipodermoids, iris colobomas

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 Anomalies of the Uveal Tract
•Aniridia
• Complete or partial absence of iris
• Misnomer, b/s at least a rudimentary iris is present
• Classic aniridia is a panocular bilateral disorder

• AD (two-thirds) or sporadic
• PAX6 gene mutations (11p13) cause classic aniridia

• Associated findings:

Foveal hypoplasia… poor fixation… nystagmus

ON hypoplasia, anterior polar cataract, ectopic lentis
Microcornea, corneal pannus, peters anomaly, ACG in 75%
WAGR syndrome
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 Anomalies of the lens

• Abnormalities in lens: shape, size, location,

development, transparency

 Congenital Aphakia
 Complete absence of lens

 Caused by failure of lens anlage

development or degeneration & absorption
of developing lens

 Secondary aphakia is marked by presence

of lens remnant
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 Congenital Cataract
 The most common of all lens anomalies, unilateral or bilateral

 Classified by morphology, genetic etiology, specific metabolic disorders, or

associated ocular anomalies or systemic findings

•Genetic & metabolic disorders (commonly bilateral cataracts) -DS, Marfan,

galactosaemia

•Maternal infection & toxicity- Rubella, CMV, varicella, radiation

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 REFERENCES
BCSC 2020/21:
 Volume 2, Fundamentals and Principles of Ophthalmology
 Volume 6, Pediatric Ophthalmology and Strabismus
 Volume 7, Oculofacial, Plastic and Orbital Surgery

DUANES’ CLINICAL OPHTHALMOLOGY

 Foundation Volume 1, Chapter 2, Prenatal Development of the Eye and Its Adnexa
 Foundation Volume 5, Chapter 5, Embryology and Anatomy of the Eyelid

LANGMAN MEDICAL EMBRYOLOGY, 14th edition

CLINICAL EMBRYOLOGY OF THE EYE, Dr Pranesh, 1st edition

KHURANA ANATOMY AND PHYSIOLOGY

Wiki EYE
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