Embryology Study Guide (Complete)

This document summarizes the key points from the full 28 pages of '[Link]',
formatted for high-yield board review.

PART II: Embryology

CHAPTER 4: Ocular Development

Highlights

• The eye develops from 2 germ layers: ectoderm and mesoderm.

• Most of the eye forms from different types of ectoderm:
◦ Surface ectoderm
◦ Neuroectoderm
◦ Neural crest cells
• Genetic cascades guide ocular development; alterations result in ocular
malformations.
• Advances in stem cell research may lead to novel treatments.

General Principles

• Embryogenesis: Successive development of cells into defined structures via

genetic programs (cascades of genes expressed in response to external cues).
• Gene Regulation:
◦ Same genes can participate in different cascades with different roles (e.g.,
activate transcription in one program, repress in another).
◦ Cascades regulated by diffusible ligands (growth factors, hormones) creating
concentration gradients.
◦ Gradients allow cells to orient position and determine program activation.
• Abnormalities: Misactivation of genetic cascades (due to pathogenic variants or
teratogens) causes embryologic abnormalities (congenital defects or lethality).
• Gastrulation: Development from single-layered blastula to multilayered gastrula.
• Germ Layers (formed during gastrulation):
1. Ectoderm: Superficial layer.
2. Mesoderm: Middle layer.
3. Endoderm: Inner layer.
• Neural Crest Cells:
◦ Ectomesenchymal cell population arising from neuroectoderm at dorsal edge
of neural tube.
◦ Transient, migratory stem cells.
◦ Can form tissues with ectodermal and mesodermal characteristics.
◦ 🔥 HIGH-YIELD: Ocular structures derived from cranial neural crest cells.

• Ocular Tissue Origins:

◦ Eye and orbital tissues develop from ectoderm, mesoderm, and neural crest
cells.
◦ 🔥 HIGH-YIELD: Neural crest cells make the largest contribution.
◦ Neural crest cells also contribute significantly to facial, dental, and cranial
structures.
◦ 🔥 HIGH-YIELD: Syndromes from neural crest maldevelopment often involve
eye + facial/dental/cranial structures.

• Neural Crest Cell Migration (Fig 4-3):

◦ Originate from junction of surface ectoderm and neuroectoderm at dorsal

edge of neural tube.
◦ Migrate laterally/ventrally.
◦ Differentiate into various structures, including:
▪ Melanocytes
▪ Dorsal root ganglia (neurons, glia)
▪ Pia and arachnoid mater
▪ Schwann cells
▪ Sympathetic ganglia
▪ Sensory ganglia of cranial nerves (e.g., CN V)

• 🔬 CLINICAL PEARL / 🔥 HIGH-YIELD: Oculoauriculovertebral dysplasia

(Goldenhar syndrome):

◦ Arises from neural crest cell maldevelopment in 1st and 2nd branchial arches.
◦ Common manifestations: Hemifacial microsomia, limbal dermoids, cleft
palate, preauricular skin tags, hearing loss, eyelid coloboma.

• Neural Crest Contribution to Eye (Fig 4-4):

◦ Neural crest cells migrate laterally and ventrally to surround the optic vesicle.
◦ Contribute significantly to tissues initially thought to be only mesodermal
(unique to head region).
 ◦ Surround the neuroectoderm (optic cup) and surface ectoderm (lens placode/
vesicle).
◦ Contribute to: Sclera, cornea (stroma, endothelium), uvea (melanocytes, iris
stroma), trabecular meshwork, orbital bones, connective tissue, orbital fat,
EOM sheaths/tendons, ciliary ganglion, Schwann cells, meningeal sheaths of
optic nerve, vasculature.

• Ectoderm Separation: After gastrulation, ectoderm separates into:

◦ Surface Ectoderm: Forms lens, corneal epithelium, conjunctival epithelium,

eyelid skin epithelium/glands/cilia, lacrimal gland, lacrimal drainage system.
◦ Neuroectoderm: Forms RPE, neural retina, optic nerve fibers/glia, ciliary
body epithelium (pigmented & non-pigmented), iris epithelium (pigmented &
non-pigmented), iris sphincter & dilator muscles, vitreous.

Table 4-1: Derivatives of Embryonic Tissues

Germ Neural Crest Surface

Neuroectoderm Mesoderm
Layer Cells Ectoderm

Bones (midline/ Epithelium/

Ciliary body
inferior orbital; glands/cilia of Extraocular
Derivatives epithelium (NPE/
parts of roof/ eyelid skin, muscle fibers
PE)
lateral rim) caruncle

Lacrimal
Iris epithelium
drainage
(anterior/ Cartilage Orbital fat
system
posterior)
epithelium

Lacrimal
Iris sphincter & Connective Vascular
gland
dilator muscles tissue of orbit endothelium
epithelium

Ciliary body
(muscle,
Vitreous Conjunctival
Ciliary ganglion stroma -
(partially) epithelium
debated, likely
NCC)

Iris stroma
Neurosensory Corneal (partially -
Orbital fat
retina epithelium
Germ Neural Crest Surface
Neuroectoderm Mesoderm
Layer Cells Ectoderm

debated, likely
NCC)

Lacrimal gland
Retinal pigment (stroma/ Temporal
Lens
epithelium (RPE) connective sclera
tissue)

Extraocular
Optic nerve Vitreous Vitreous
muscle sheaths
(axons, glia) (partially) (partially)
& tendons

Vasculature
(muscle/
Choroid
connective
(vascular
tissue sheaths of
components)
ocular/orbital
vessels)

Corneal stroma
& endothelium

Melanocytes
(uveal,
epithelial)

Schwann cells of
ciliary nerves

Sclera (except
temporal)

Trabecular
meshwork

Iris stroma

Vitreous
(partially)
 Germ Neural Crest Surface
Neuroectoderm Mesoderm
Layer Cells Ectoderm

Choroid (stroma,
melanocytes)

Meningeal
sheaths of optic
nerve

Note: Some contributions, particularly mesoderm vs. neural crest for uveal stroma and
ciliary muscle, are debated or complex.

Eye Development Timeline (Fig 4-6, Table 4-2)

• Day 22 (Start Week 4):

◦ Optic primordium appears in neural folds.
◦ Two optic sulci (neuroectoderm) develop, deepen to form optic pit -> optic
vesicles.
• Day 25:
◦ Optic vesicle evaginates.
◦ Neural crest cells migrate to surround vesicle.
• Day 27 (End Week 4):
◦ Optic vesicle contacts surface ectoderm.
• Day 28:
◦ Optic vesicle induces overlying surface ectoderm to thicken -> lens placode.
• Day 29 (Week 5):
◦ Optic vesicle invaginates -> forms bilayered optic cup (inner layer = neural
retina, outer layer = RPE).
◦ Lens placode invaginates -> lens pit -> lens vesicle.
◦ Embryonic fissure (optic fissure) forms ventrally in optic cup and stalk.
◦ Hyaloid artery (mesoderm) enters via embryonic fissure.
◦ Ectomesenchyme (neural crest + mesoderm) fills space between cup and
surface ectoderm (future anterior segment) and surrounds posterior cup
(future choroid, sclera).
• Day 37 (Week 6):
◦ Lens vesicle pinches off from surface ectoderm.
◦ Posterior lens vesicle cells elongate -> form primary lens fibers, filling vesicle
cavity.
◦ Surface ectoderm reforms -> future corneal epithelium.
◦ Inner layer of optic cup -> future neural retina.
 ◦ Outer layer of optic cup -> future RPE.
◦ Space between layers -> future subretinal space.
• Week 7 (Day 44):
◦ Embryonic fissure closes.
◦ Eyelid folds begin forming.
◦ Neural crest cells migrate between surface ectoderm and lens vesicle -> future
corneal endothelium and stroma.
◦ Mesenchyme around optic cup differentiates -> inner vascular layer (choroid)
and outer fibrous layer (sclera).
◦ Tunica vasculosa lentis forms around lens.
• Week 8:
◦ Ganglion cell axons grow towards brain, forming optic nerve.
◦ Eyelids fuse.
◦ Anterior chamber forms.

Table 4-2: Chronology of Embryonic and Fetal Development of the Eye

Size
Time Event
(mm)

1.5–
Day 22 Optic primordium appears in neural folds.
3.0

Optic vesicle evaginates. Neural crest cells migrate to surround

Day 25
vesicle.

Day 28 Vesicle induces lens placode.

Eyelid folds appear. Optic cup forms. Lens vesicle forms.

4–5
Embryonic fissure forms. Hyaloid artery enters. RPE pigmented.
weeks
Primary vitreous forms.

Embryonic fissure closes. Lens vesicle separates from surface

ectoderm. Primary lens fibers form. Neural crest migration
6 weeks 12
(corneal endothelium/stroma). Scleral condensation begins.
Optic nerve axons reach brain.

Secondary lens fibers form. Secondary vitreous forms. Retinal

7 weeks 17–20 differentiation begins. Eyelid folds grow. Nasolacrimal duct
forms.

8 weeks 23–30 Tertiary lens fibers form. Retinal vascularization begins.

 Size
Time Event
(mm)

Eyelids fuse. Iris develops. Ciliary body develops. Bruch

3
50–60 membrane forms. Sclera covers globe. Retinal layers
months
differentiate. Macula differentiation begins.

4 100– Foveal depression begins. Retinal vessels reach ora serrata.

months 110 Medullation (myelination) of optic nerve begins posteriorly.

5
150 Retinal layers complete.
months

6 200–
Eyelids separate. Iris pigmentation begins.
months 240

7 Pupillary membrane disappears. Retinal vessels mature. Macula

250
months develops further.

8
300 Lens fibers compact.
months

9
350 Iris pigmentation continues. Myelination reaches lamina cribrosa.
months

Eye approximately 75% of adult size. Macula development

Birth continues postnatally. Myelination of optic nerve completes
postnatally (up to ~1 month).

Embryonic Fissure and Coloboma

• Optic cup invagination is asymmetric, containing a ventral embryonic fissure.

• Fissure facilitates entry of mesodermal and neural crest cells (for hyaloid artery,
etc.).
• Closure sequence: Center first, then zips anteriorly and posteriorly (completes by
week 6).
• 🔥 HIGH-YIELD: Failure of embryonic fissure closure leads to coloboma (iris, lens,
retina, choroid, optic nerve).
• Location of fissure closure corresponds to the inferonasal quadrant, where
colobomas typically occur (Fig 4-8).
• 🔬 CLINICAL PEARL:
◦ Anterior colobomas (iris, anterior sclera) are most common.
◦ Posterior colobomas (optic nerve, retina, choroid) are less common.
 ◦ Central colobomas are least common.

Lens

• Formation:
◦ Begins with proliferation of surface ectoderm -> lens plate.
◦ Invagination of plate -> lens pit.
◦ Pit deepens, closes anteriorly, detaches -> lens vesicle (Fig 4-6C, D).
◦ Remaining surface cells -> corneal epithelium (Fig 4-6D).
◦ Invading neural crest cells -> corneal endothelium & stroma (Fig 4-6E).
• Lens Vesicle Structure (Fig 4-9):
◦ Single layer of cuboidal cells around a lumen, within optic cup.
◦ Anterior cells: Remain cuboidal, single-layered (anterior lens epithelium -
LE).
◦ Posterior cells: Elongate -> primary lens fibers (PLF), fill vesicle cavity ->
form embryonal nucleus.
◦ Outer cells create basement membrane -> lens capsule.
• Lens Capsule:
◦ True basement membrane surrounding cellular component.
◦ Transparent.
◦ Thickest at equator, thinnest posteriorly.
◦ Composition: Type IV collagen, GAGs.
◦ 🔥 HIGH-YIELD: Elasticity key for accommodation.
• Lens Growth:
◦ Anterior lens epithelium continues forming new secondary lens fibers (SLF)
throughout life (at lens bow region) -> lenticular thickening with age (Fig
4-9D).
• Tunica Vasculosa Lentis:
◦ Branching vessel network derived from hyaloid artery supporting lens
vesicle development.
◦ 🔥 HIGH-YIELD: Failure to regress leads to:
▪ Pupillary membranes (common finding).
▪ Persistent fetal vasculature (PFV) (malformation, associated with
lenticular opacity, abnormal eye development).
• Zonular Fibers:
◦ Form as part of tertiary vitreous.
◦ Derived mostly from mesoderm and ectoderm (ciliary epithelium).
Posterior Segment

Retina

• Origin (Fig 4-10):

◦ Inner layer of optic cup -> Neural retina (NR).
◦ Outer layer of optic cup -> Retinal pigment epithelium (RPE).
◦ Opposing surfaces are ciliated:
▪ Inner layer cilia -> develop into photoreceptors.
▪ Outer layer cilia -> regress.
• Retinal Attachment:
◦ 🔬 CLINICAL PEARL / 🔥 HIGH-YIELD: Neurosensory retina and RPE appose
but lack covalent linkage.
◦ Attachment maintained by: Hydrogen bonds, electrostatic forces, osmotic
gradient.
◦ Potential space exists (subsensory/subretinal space).
◦ Fluid accumulation -> retinal detachment.
• Neural Retina Development (Fig 4-11):
◦ Driven by overlapping genetic cascades (e.g., Nrl transcription factor for rod
development).
◦ Occurs concentrically: Center -> periphery.
◦ Lamination (8-12 weeks): Inner and Outer Neuroblastic Layers (INBL, ONBL).
▪ INBL -> Ganglion, Müller, Amacrine cells.
▪ ONBL -> Bipolar, Horizontal cells, Photoreceptors.
◦ Ganglion cells: First to differentiate (proliferate rapidly early 2nd trimester).
◦ Limiting Membranes (ILM, ELM): Develop as cells cease proliferation and
differentiate.
• Retinal Vasculature (Fig 4-12):
◦ Develops from remnants of hyaloid artery -> becomes central retinal artery.
◦ Development involves vasculogenesis (from mesenchymal precursors) and
angiogenesis (from existing vessels).
◦ Endothelial cells organize posteriorly; vessel development follows concentric
pattern (center -> periphery).
◦ 🔬 CLINICAL PEARL / 🔥 HIGH-YIELD: Concentric vascular development
basis for ROP zones (I-III).

Retinal Pigment Epithelium (RPE)

• Forms from proliferating columnar epithelial cells (outer layer of optic cup).
• Cells create lateral tight junctions.
• Deposit basement membrane -> becomes inner layer of Bruch membrane.
 • 🔥 HIGH-YIELD: Only pigmented tissue not derived from neural crest cells
(originates from neuroectoderm near neural crest boundary).

Optic Nerve (Fig 4-12)

• Develops from optic stalk (neuroectoderm connecting optic vesicle to forebrain).

• Optic stalk regulates cell migration via ligands/receptors.
• Structure: Neuroectodermal cells surrounded by neural crest cells.
• Week 6: Neuroectodermal cells vacuolate/degenerate -> space for ganglion cell
axons from inner retina.
• Surrounding Cells:
◦ Neural crest cells -> Meninges (dura, arachnoid, pia).
◦ Neuroectodermal cells -> Oligodendrocytes (form myelin sheaths).
• 🔥 HIGH-YIELD: Optic nerve myelinated by oligodendrocytes (like CNS), not
Schwann cells (like PNS). This makes it susceptible to demyelinating diseases like
optic neuritis (associated with MS).

Vitreous (Fig 4-13, 4-14)

• Develops from mesodermal and ectodermal components.

• Connective fibers: Likely from neural crest cells of inner optic cup.
• Hyaloid vasculature: From mesodermally derived cells.
• Primary Vitreous:
◦ Earliest vitreous.
◦ Forms central conical structure.
◦ Contains hyaloid vasculature.
• Secondary Vitreous:
◦ Forms from hyalocytes.
◦ Surrounds primary vitreous.
◦ Avascular, gel-like.
◦ Forms bulk of adult vitreous.
• Tertiary Vitreous (Zonules):
◦ Forms last.
◦ Develops from ciliary body epithelium (neuroectoderm) and possibly
mesenchyme.
◦ Forms the suspensory ligaments (zonules) of the lens.
• Hyaloid System Regression:
◦ Hyaloid artery and tunica vasculosa lentis regress during fetal development.
◦ Remnants can persist:
▪ Mittendorf dot: Small opacity on posterior lens capsule.
▪ Bergmeister papilla: Tuft of glial tissue on optic disc.
▪ Persistent pupillary membrane: Strands across pupil.
 ▪ Persistent fetal vasculature (PFV): More severe failure of regression.

Uvea

• Also called uveal tract.

• Pigmented vascular layer of the eye.
• Develops from mesoderm and neural crest cells.
• Comprises: Iris, Ciliary Body, Choroid.
• 🔥 HIGH-YIELD: Epithelial layers of ciliary body and iris are neuroectoderm, not
part of the uvea.
• Pigmentation: From neural crest-derived melanocytes.
• Blood vessels & ciliary muscle: Derived from mesoderm.

Ciliary Body and Iris (Fig 4-15)

• Formation:
◦ Anterior optic cup margin: Surrounding mesoderm proliferates, pushing
neuroectoderm inward/centrally between corneal endothelium and anterior
lens.
◦ Gives rise to ciliary body and iris epithelium.
• Ciliary Body:
◦ Mesodermal proliferation -> forms ciliary muscle.
◦ Neuroectoderm infolds -> forms ciliary processes.
◦ Ciliary Epithelium (Neuroectoderm):
▪ Inner Non-Pigmented Epithelium (NPE): Faces posterior chamber.
Continuous with neural retina posteriorly and posterior iris epithelium
anteriorly.
▪ Outer Pigmented Epithelium (PE): Continuous with RPE posteriorly.
• Iris:
◦ Iris Epithelium (Neuroectoderm):
▪ Posterior Iris Epithelium (PIE): Continuous with NPE of ciliary body.
Acquires pigment during development (pupil margin -> root).
▪ Anterior Iris Epithelium: Remains non-pigmented. Forms iris dilator
muscle.
◦ Iris Stroma & Vasculature: From anterior mesenchymal elements
(mesoderm, incorporating tunica vasculosa lentis remnants).
◦ Iris Sphincter Muscle: Develops from neuroectoderm near pupillary margin
(derived from optic cup neuroectoderm, like dilator).

Choroid

• Forms from condensation of neural crest cells and mesoderm surrounding the
optic cup (inner aspect).
 • Layers (develop sequentially):
1. Choriocapillaris: Inner layer of small, fenestrated blood vessels.
2. Outer Layer: Larger vessels (form vortex veins, branches of posterior ciliary
circulation).
3. Middle Layer: Arterioles (form between choriocapillaris and outer layer).
• Melanocytes: Develop later in gestation.

Cornea, Anterior Chamber, and Sclera

Cornea and Anterior Chamber (Fig 4-17, Table 4-3)

• Corneal Epithelium: Surface ectoderm closes over lens pit.

• Neural Crest Cell Migration (3 Waves):
1. First Wave: Forms corneal endothelium (passes between surface ectoderm
and lens vesicle).
2. Second Wave: Forms keratocytes of corneal stroma (passes between
endothelium and epithelium).
3. Third Wave: Contributes to iris stroma (neural crest + mesoderm).
• Anterior Chamber Angle:
◦ Forms where corneal endothelial cells meet developing iris -> angle recess.
◦ Trabecular Meshwork (TM) & Schlemm Canal (SC): Develop from
mesenchymal cells posterior to recess.
◦ SC Endothelium: Derived from adjacent capillaries (form episcleral venous
plexus).
◦ Aqueous veins drain aqueous to venous circulation.
◦ TM beams mature and stratify.
◦ 🔥 HIGH-YIELD: Abnormal development implicated in congenital glaucoma
and anterior segment dysgenesis.
◦ Scleral Spur: Forms between TM and ciliary muscle as angle develops (Fig
4-15C, D).

Table 4-3: Waves of Neural Crest Cell Migration in Anterior Segment Development

Wave Timing Cells Migrate Between Forms

Surface Ectoderm & Lens

1st ~Week 6-7 Corneal Endothelium
Vesicle

Corneal Endothelium &

2nd Follows 1st Corneal Stroma (Keratocytes)
Epithelium

3rd
 Wave Timing Cells Migrate Between Forms

Follows Iris Stroma (along with

2nd mesoderm)

Sclera

• Forms from mesoderm (temporal sclera) and neural crest-derived

ectomesenchyme.
• Condenses around developing optic cup, joining cornea near equator.
• Continues to expand posteriorly.
• Scleral Spur & Tenon Capsule: Form later, at time of EOM insertion.

Development of the Extraocular Muscles, Adnexa, and Orbit

Extraocular Muscles (EOMs)

• Form from paraxial and prechordal mesoderm.

• Development guided by cues from developing eye and surrounding neural crest
mesenchyme.
• 🔥 HIGH-YIELD: Interactions between optic cup, mesoderm, and neural crest cells
are crucial for proper EOM development/organization.
• Anomalous EOM development often occurs if optic cup fails to form properly (e.g.,
microphthalmia spectrum).

Iris Development (Fig 4-16)

• Sphincter & Dilator Muscles: Derived from neuroectoderm (anterior iris

epithelium for dilator).
• Stroma & Melanocytes: Derived from neural crest cells.
• Vasculature: Derived from mesoderm (pupillary membrane remnants).

Cornea Development (Fig 4-17)

• Epithelium: Surface ectoderm (2 layers initially, ~3 by 3 months).

• Endothelium: First wave of neural crest cells (~day 39).
• Stroma (Keratocytes): Second wave of neural crest cells (~week 7), initially few
collagen fibrils, ~25-30 layers by 3 months.
• Descemet Membrane: Forms between posterior stroma and endothelium (~3
months).
• Bowman Layer: Develops later, postnatally.
Adnexa Development

Eyelids (Fig 4-18)

• Formation (Start 4-5 weeks): Proliferation of surface ectoderm near future outer
canthus -> skin folds surrounding neural crest mesenchyme.
• Infiltration: Mesodermal mesenchyme infiltrates -> forms palpebral musculature
(orbicularis, levator).
• Fusion (Weeks 8-10): Eyelid folds grow and fuse (starts nasally).
• Glands & Cilia: Develop after fusion.
• Separation (Month 5-7): Adhesions break down (coincident with sebaceous gland
secretion, epithelial cornification).

Lacrimal Gland

• Formation (Weeks 6-7): Solid epithelial cords proliferate from conjunctival basal
cells (temporal fornix).
• Acini: Neural crest mesenchyme aggregates at cord tips -> differentiate into acini.
• Ducts (Month 3): Form by vacuolation of cord cells -> develop lumina.
• 🔥 HIGH-YIELD: Reflex tear production begins ~20+ days after birth (newborns cry
without tears).

Orbit Development

• Involves ectoderm, mesoderm, and neural crest cells.

• Week 4: Frontonasal and maxillary processes (neural crest) surround optic cups.
• Orbital Contents: Bones, cartilage, fat, connective tissues develop from these
neural crest cells.
• Orbital Bones: All are membranous bone except the sphenoid (cartilaginous
origin).
• Ossification: Begins month 3, fusion occurs months 6-7.

Genetic Cascades and Morphogenic Gradients

• Early Transcription: Embryonic genome transcribed after midblastula transition;

initially relies on maternal mRNA.

Homeobox (HOX) Gene Program

• HOX Genes: Contain conserved ~180 bp DNA segment encoding 60-aa

homeodomain (specific DNA-binding capability).
• Function: Act as master regulators/switches of gene transcription by binding
promoter sequences -> drive cell fate and tissue/organ development.
 • Key Eye Development HOX Genes (Pathogenic variants -> Conditions):
◦ 🔥 PAX6: Master switch for eye development. Expressed early in primordial
eye field. (-> Aniridia (Fig 4-19), Peters anomaly, coloboma, microphthalmia).
◦ PAX2: (-> Renal coloboma syndrome).
◦ RAX (Retina and Anterior Neural Fold homeobox): (-> Microphthalmia).
◦ PITX2 (Paired-like homeodomain 2): (-> Peters anomaly, Axenfeld-Rieger
syndrome).

Growth Factors, Diffusible Ligands, and Morphogens

• Provide real-time signals for developing eye cells.

• Morphogens: Diffusible extracellular factors active in early development.
• Important Factors:
◦ Retinoic Acid (RA)
◦ Wnt
◦ Fibroblast Growth Factors (FGFs)
◦ Hedgehog family (Shh, Ihh)
◦ Insulin-like Growth Factor (IGF)

• Mechanism Groups:

◦ Group 1 (e.g., RA): Interact with intracellular receptors -> directly regulate
gene expression.
◦ Group 2 (e.g., Wnt, FGF, Shh, IGF): Bind cell-surface receptors -> trigger
intracellular signaling cascades -> activate/repress transcription factors.

• Signaling Pathways:

◦ Retinoic Acid (RA): Crucial for anterior segment development, neural crest
cell migration.
◦ Wnt Signaling:
▪ 🔥 HIGH-YIELD: Defects cause Familial Exudative Vitreoretinopathy
(FEVR) (incomplete peripheral retinal vascularization -> vitreous
hemorrhage, tractional RD).
◦ FGF Signaling: Regulates MITF (Microphthalmia-associated transcription
factor) expression in optic cup -> balances neural retina vs. RPE development.
◦ Hedgehog (Shh, Ihh): Involved in optic nerve development, retinal cell fate.
◦ IGF: Role in ocular growth.
• Morphogenic Gradients: Cells respond differently based on ligand concentration -
> determines cell fate.
Future Directions

• Stem Cell Biology: Arose from embryologic studies.

• Human Embryonic Stem Cells (hESCs):
◦ First cultured 1998 (from spare IVF blastocysts).
◦ Range from totipotent -> pluripotent -> multipotent (lineage-restricted
progenitor cells, e.g., limbal stem cells).
◦ Can self-renew via asymmetric division.
• Induced Pluripotent Stem Cells (iPSCs):
◦ Generated from adult somatic cells (e.g., skin).
◦ More accessible, less politically charged model for studying pluripotency.
• Retinal Organoids:
◦ 3D neural retina generated in vitro from hESCs/iPSCs.
◦ Follow normal embryonic steps (optic vesicle invagination, optic cup
formation) -> complex, stratified retinal tissue + RPE.
◦ Allow study of human retinal development/disease outside the organism.
◦ Successfully used to model: Microphthalmia, Best disease, Gyrate atrophy,
LCA, RP.
• Other Ocular Tissues: Stem cell lines used for corneal epithelium, endothelial
regeneration.
• Future Therapies: Regenerative transplantation likely to use lineage-restricted
progenitor cells (↑ success, ↓ cancer risk).