Embryology - Part 2

Development of the Cornea

What role does the developing anterior epithelium of the lens play in corneal development?

Induction by the developing lens anterior epithelium signals multiple steps in corneal development at the time when the lens vesicle separates from the surface ectoderm

Development of the Cornea

What occurs at 39 days of Corneal Development?

• epithelium is a 2-layered structure resting on a basal lamina

• endothelium (2-3 layers)

• both separated by a narrow cellular space

Development of the Cornea

What occurs at 7 weeks of Corneal Development?

• Mesenchyme (fibroblasts) from the periphery migrates between epithelium and endothelium to form the stroma precursor

  • Fibroblasts → collagen fibers secreted

• Stroma is multilayered (5-7 layers thick)

Development of the Cornea

What occurs at 7.5 weeks of Corneal Development?

Mesenchyme (fibroblasts) is arranged in 4-5 incomplete layers

• some collagen fibrils begin to appear

  

Development of the Cornea

What occurs at 3 months of Corneal Development?

• epithelium has 2-3 layers

• stroma has 25-30 layers of fibroblasts (keratoblasts), which are more regularly arranged in the posterior half

• Descemet's membrane is thin and uneven b/w most posterior keratoblasts & endothelium

• Endothelium is 1 layer

Development of the Cornea

What occurs at 4.5 months of Corneal Development?

• Wing cells begin to form above basal epithelial cells.

• Bowman's layer begins to emerge under the basal lamina

• anterior portion of the stroma stays disorganized, while the posterior stroma becomes more organized

• Descemet’s membrane becomes well-developed

  

Development of the Cornea

What occurs at 7 months of Corneal Development?

Has adult cornea structure

• some superficial keratoblasts in stroma stay randomly oriented

• Collagenous lamellae in the rest of the stroma are in parallel arrays, with few gaps

  • gaps get filled by 9 months

• Descemet's membrane is fully formed and continuous

Development of the Cornea

What is the role of the First wave of mesenchyme?

- Migrates into the space b/w the corneal epithelium & lens → forms corneal endothelium

• By week 8, the mesenchyme proliferates and forms 2 cell thick layers (cuboidal cells) → cells give rise to fibroblasts which produce collagen & ground substance of the stroma

Development of the Cornea

What is the role of the Second wave of mesenchyme?

→ Migrates b/w the developing epithelium & endothelium

• this wave helps form the aq humor

Development of the Cornea

What is the role of the Third wave of mesenchyme?

migrates into the area b/w the endothelium and lens → pupillary membrane development

Development of the Cornea

Where do all 3 waves of mesenchyme all originate from?

Neural crest

Development of the Cornea

How does the Corneal Curvature change at birth vs 6 months?

→ Rapid growth of the corneal stroma increases curvature relative to the rest of the globe

• At birth: curvature is 55D (circular and steep)

• By 6 months: curvature is 44D

Development of the Cornea

When do corneal nerves enter the developing cornea?

3 months

Development of the Cornea

Describe the development of the Corneal nerves.

Month 3: Corneal nerves enter cornea

Month 5: Nerves grow through the stroma to reach the epithelium

Month 5 to birth: Nerves increase & branch → diffuse whorl network formed in the stroma and subepithelial layers

• by the time the eyelids open at 5 months, the cornea is highly innervated

Development of the Sclera

Describe the development of the Sclera.

1. First develops anteriorly from condensations in the mesenchyme near the limbus

2. Month 3: Growth continues as it surrounds the optic nerve

3. Month 4: CT fibers cross the posterior scleral foramen through the optic nerve, producing the 1st CT strands of the lamina cribrosa

4. Month 5: Sclera (and scleral spur) is well-differentiated

Development of the Sclera

Describe the role of Induction in Scleral development.

RPE cells are needed to initiate scleral development, but not required to complete it

• If fetal fissure fails to close, scleral formation continues, but may result in an iris coloboma

Development of the Sclera

What is Scleral development largely controlled by?

1. IOP

2. Aq formation

Development of the Choroid

Outline the Choroid Development.

Month 2: Choroid vessels appear

Month 3: Fenestrations in the vessels, covered by a diaphragm (thin membrane) appear

Month 4: Bruch’s membrane develops (prevents choroid vessels from entering the retina)

Month 5: Layers of the large & medium vessels are evident → vortex veins

• SPCA are evident + begin to anastomose → Circle of Zinn

Appears last: BM of the choriocapillaris

Development of the Ciliary Body 

Describe the development of the Ciliary body. 

• Outer optic cup → outer pigmented epithelium (3rd month)

• Inner optic cup → non-pigmented epithelium (NPE) + folds

  • Folds → ciliary processes

  • Tight junctions (zonula occludens) appear in NPE (3rd month)

• LPCA & ACA anastomosis → Major arterial circle (4th month)

• Neural crest → ciliary muscle (5th month)

Development of the Choroid

When does Aq humor production start?

4–6 months

Development of the Iris

How does the Optic Cup contributes to the development of the Iris?

1) Lip of optic cup elongates b/w lens + developing cornea (end of 3rd month) 

• Outer optic cup layer → anterior iris epithelium

• Inner optic cup layer → posterior iris epithelium

2) 2 epithelial layers are joined apex-to-apex (via intercellular junctions)

Development of the Iris

How do the spincter & dilator muscle contributes to the development of the Iris? (Mention when this occurs too)

Sphincter muscle (5th month)

• Cells from anterior iris epithelium break away into stroma → differentiate into smooth muscle fibers → iris sphincter

Dilator muscle (6th month)

• Forms within anterior iris epithelium

Both sphincter & dilator fully developed by birth

Development of the Iris

What’s the timeline of Iris pigmentation development? (Mention when this occurs too)

Week 10: Pigmentation begins

7 months: Pigmentation complete

Postnatal: Darkening up to ~6 months via stromal melanocytes; stromal maturation until ~7 years

Development of the Iris

How does the ABL & Stroma form?

• Mesenchymal cells line up → ABL (with gaps)

• Collagen begins to accumulate → iris stroma

  • More densely packed stromal melanocytes = darker iris color

Development of the Iris

When and where is the Pupillary Membrane formed?

→ Formed during Month 3 from 3rd wave mesenchyme + branches of major circle of iris

• forms b/w lens epithelium & corneal endothelium

• has 3–4 vascular arcades present by the end of Month 5

Development of the Iris

How does pupillary membrane atrophy occur? (Mention dates)

Month 6: Central vessels become atrophy + become bloodless

By ~8.5 months: Central vessels fragment & disappear

• Peripheral vessels contribute to the minor arterial circle of iris

Note: Breakdown of central vessels = key sign pupil is forming shape

Development of the Clilio Iridic Circulation

When does vascular supply of the iris & pupillary membrane begins developing? What supplies it with blood?

8 months via LPCA

Development of the Clilio Iridic Circulation

What’s the role of the LPCA in the vascular supply of the Cilio Iridic circulation?

→ help form the Major Arterial Circle

MAC provides vascular supply to the:

• Anterior segment

• Pupillary membrane

• Iris

• ciliary body

Development of the Anterior Chamber.

How is the Anatomical space of the Anterior Chamber created? When does this occur?

During weeks 7 and 8

1. Undifferentiated mesenchymal tissue b/w corneal endothelium & anterior surface of iris stroma resorb from the centre to the periphery 

2. This creases large gaps → anterior chamber

This entire process is completed by remodeling the tissues

Development of the Anterior Chamber

What growth factors contribute to the growth of the Anterior Chamber?

Every tiny kitty has fuzzy paws

Epidermal (EGF)

Transforming (TGFβ)

Keratinocyte (KGF)

Hepatocyte (HGF)

Fibroblast (FGF)

Platelet-derived (PDGF)

Development of the Anterior Chamber

Where are growth factors presented?

Why is the production of growth factors from corneal cells important?

→ Found in the tear fluid & aq humour

• allow for the maintenance and renewal of normal anterior eye tissues

Development of the Anterior Chamber

What are the Major theories in the creation of the Anterior chamber angle?

1) Reorganization Theory: Cellular differentiation and reorganization of the mesenchymal/neural crest cells → mature meshwork of beams & spaces formation

2) Atrophy and Resorption Theory: Cell death/resorption → intertrabecular space formation

Development of the Anterior Chamber

What is the TM? Describe its development.

→ triangular mass of mesenchymal cells

Month 4: becomes more organized 

Month 9: trabecular beams and pores are well developed

• spaces & pores formed by programmed cell death

Development of the Anterior Chamber

What is Schlemm’s canal derived from? Describe its development.

→ Derived from the deep scleral plexus

4th month: TJ appear in the canal’s endothelial lining

7th month: Canal is fully formed in some quadrants

8th month: Giant vacuoles appear in the endothelium

9th month: Complete circular canal (Schlemm’s canal) is formed

Development of the Anterior Chamber

How does the endothelial lining of the anterior chamber change during development, and what effect does this have on aqueous outflow?

Anterior chamber is lined by a continuous endothelium covering the TM & iridocorneal angle

Month 7: Endothelial membrane is continuous → no aq outflow

Month 9: Endothelial membrane is discontinuous → allows aq outflow

Development of the Vitreous

What is the origin and composition of the Primary Vitreous?

• Origin: mesenchymal and ectodermal tissue

• Composition: Fibrils (from lens and retina) & components from degenerating hyaloid system

  

Development of the Vitreous

Describe the Secondary Vitreous.

→ made by the neural retina and hyalocytes from the 1er vitreous

• has a fibril network and primitive hyalocytes

• encloses the 1er vitreous within the atrophying hyaloid vessels → forms the funnel-shaped Cloquet’s canal

  • Apex - faces optic disc

  • Base - faces posterior lens

  • Fully formed by Month 4 and remains in adults

Development of the Vitreous

Describe the Tertiary Vitreous.

Condensed fibrils of the 2er vitreous (anterior to the marginal bundle of Druault) elongate → lens zonules/suspensory ligament of the lens (aka 3er vitreous)

Development of the Optic Nerve

Describe the Optic nerve development.

Optic stalk connects the optic vesicle to the forebrain

• Outer stalk layer → forms neuroglial sheath surrounding the nerve

• Inner layer → glial cells (oligodendrocytes, astrocytes) & lamina cribrosa components

  • apoptosis of the cells in inner layer → space for RGC axons to enter the stalk

Development of the Optic Nerve

Describe the further maturation that occurs in Optic nerve development.

Months 2 - 8: Axon ↓50% due to apoptosis

• allows glial & CT to enter optic nerve

• RGC axons fill the optic nerve lumen and grow toward the LGN

Month 5: Myelination begins

Month 6: Myelination continues to the optic chiasm & reaches the lamina cribrosa 1–3 months after birth

What is Bergmeister’s Papilla?

Glial tissue that remains on the optic nerve head

What is Physiological Cupping?

Congenital disorder caused by:

• scleral optic canal

• glial atrophy of Bergmeister’s papilla

- ↑ cupping = ↑ atrophy

Development of Ocular Adnexa

Describe how the Eyelid develops.  

Month 2: Folds of surface ectoderm grow towards eachother over the cornea

Month 3: Folds meet & fuse (stay fused)

- Tarsal plates = 1st visible structures

• Epithelial buds from the eyelid margins grow into the tarsal plates → form Meibomian glands

Month 4: Zeis and Moll glands develop

- Mesenchyme → Tarsal plates, orbicularis, levator & Müller’s muscle

Development of Ocular Adnexa

Why do the eyes stay fused during development?

• Protects eye from amniotic fluid

• Prevents keratinization/hardening of cornea & conjunctiva

Development of Ocular Adnexa

What “opens” the fused eyelids?

During 5th-6th month:

Desmosomes at lid margins break down → eyelid separation

Development of Ocular Adnexa

Describe the development of Conjunctiva.

Weeks 9-10: Conjunctiva differentiates within the lid margins after lid fusion

- Nonkeratinized epithelium lines the inner eyelid surface

• Palpebral conjunctiva: lines under the lid

• Bulbar conjunctiva: joins the corneal epithelium

Weeks 10-11: Unicellular goblet cells appear

Development of Ocular Adnexa

How do Accessory lacrimal glands form?

via inward budding from the palpebral conjunctival epithelium

Development of Orbit

Where do Orbital bones originate from?

→ derived from cranial neural crest cells

• these cells migrate into the head, surround the developing eye, and form:

  • Frontonasal process → forms Lacrimal + Ethmoid bones  

  • Maxillary processes → forms Lateral wall and floor

Development of Orbit

What processes allows for the formation of the Orbital bones?

Most orbital bones form via intramembranous ossification

• Exception: Sphenoid & Ethmoid bones (endochondral ossification)

Development of Orbit

What is the timeline of the ossification process of Orbital bones?

6th week: Ethmoid is the 1st bone to ossify

3rd month: All bones begin to ossify

6th–7th month: All bones finish ossification

Development of EOMs

Where do EOMs originate from?

Origin: Head mesoderm

• Myoblasts migrate around the developing eye → differentiate into striated muscle fibers

Development of EOMs

What is EOM formation influenced by?

→ interactions w/ mesenchymal condensations

3 condensations on each side of head:

• 1 Pre-mandibular

• 2 Maxillomandibular

Development of EOMs

Make a chart on the EOMs derived from the Pre-mandibular & Maxillomandibular condensations.

Development of EOMs

When does the EOM tendon attach to the globe?

Mid-3rd month

• where they then fuse to sclera near equator

Development of EOMs

How does Tenon's capsule form?

via condensation around eyeball

Development of EOMs

When are Tendinous sheaths formed by?

~18 months

Development of the Nasolacrimal System

Describe the timeline of the Nasolacrimal system formation.

Week 5: Ectoderm invaginates b/w the lateral nasal process & maxillary process

• these 2 processes fuse along the nasolacrimal groove

• Surface ectoderm folds in and closes off → forming a “cord” that gets buried under the skin

Week 6: Cord extends from medial canthus to nasal cavity → differentiates into nasolacrimal system components

Week 12: Cannalization - Cord proliferates toward:

• Medial canthus

• Inferior medial nasal cavity

By 7 months: Canalization almost complete

• Puncta perforation usually occurs before birth

Development of the Nasolacrimal System

During the cord proliferation/cannalization, what structures become recognizable?

• Canaliculi

• Lacrimal sac

• Lumen began to form in lacrimal sac

• Nasolacrimal duct

Development of the Nasolacrimal System

Describe how the Lacrimal gland develops. When is it fully developed?

→ Develops from epithelial buds from conjunctiva of superior fornix

• Continues developing after birth

• possible origin = neural crest

• Full development: ~3–4 years old

What is Dacryostenosis?

blocked tear duct due to incomplete canalization of nasolacrimal duct 

• Symptoms: epiphora or watery eyes

What is Congenital Lacrimal Fistula?

→ Small opening near the inner corner of the eye

• caused by an epithelial tract connecting the skin to the canaliculi, lacrimal sac or nasolacrimal duct

  • instead of canaliculi to tear duct  

• Symptoms: Asymptomatic or epiphora, watery eyes

What is Punctal Atresia?

→ puncta is closed/absent

• caused by genetics

• Symptoms: epiphora → tears overflow

Development of Blood Vessel Permeability and Barriers

Where is the Blood-Aqueous Barrier found?

Iris & ciliary body

Development of Blood Vessel Permeability and Barriers

What forms the Inner Blood-Retinal Barrier?

→ formed by retinal capillary endothelial cells with TJ

• Supported by Müller cells & pericytes

-Nourishes Inner retina

Development of Blood Vessel Permeability and Barriers

What forms the Outer Blood-Retinal Barrier?

→ Formed by RPE cells

• TJ separate retina from choroid

-Nourishes Outer retina

Development of Blood Vessel Permeability and Barriers

Blood-Retinal and Blood-Aqueous Barriers are recognized early in development in the TJ formed in the:

• RPE

• Non-pigmented ciliary epithelium

• Capillaries of the iris and retina

Development of Blood Vessel Permeability and Barriers

What are fenestrations and their role in blood vessel permeability?

• Establish vessel permeability in:

  • Capillaries of ciliary processes

  • Choriocapillaris

• appear early in the gestational period

• Function: Allow nutrients to leak through & nourish tissues

What is Iris Coloboma?

→ embryonic fissure fails to close during 5th WG → "keyhole-shaped" pupil

• rest of the iris develops normally

• can be associated with colobomas of the ciliary body, choroid, retina, or optic nerve

What is Retinal Coloboma?

→ Colobomas affect the retina (sensory & RPE) also involves the choroid b/c its differentiation depends on an intact RPE layer

• can result in → vision loss in specific visual fields, low vision 

• common complications = Retinal detachment & cataract

What causes congenital cataracts during lens development?

1er fiber defect: Failure of proper elongation & alignment → cataract of 1er fibers

2er fiber defect: Interference → sutural cataracts

Viral cause: Maternal rubella infection (4th–7th week) → affects lens

• cataract may be present at birth or appear later (virus can persist up to 3 years)

What causes Ocular albinism?

→ occurs due to gene-related defects in melanin production, affecting one or both types of melanocytes

• Melanin from the RPE influences normal sensory retina development

  • without it, many retinal abnormalities occur at birth

What retinal abnormalities are seen in ocular albinism?

• Underdeveloped macula

• No fovea

• ↓ rods

• Abnormal optic nerve projection LGN (results in binocular issues)

  

What causes Retinopathy of Prematurity (ROP)?

Premature infants exposed to high O₂: develop vasoconstriction of immature retinal vessels → vessels fail to develop

After O₂ removal: Vasoproliferation occurs → new vessels form which are leaky with poorly formed endothelial TJ

What are the 2 Phases of Retinopathy of Prematurity (ROP)?

Phase 1: Hyperoxia → loss of nutrients/growth factors → vessel growth stops → (Stage 1–2)

Phase 2: Hypoxia → ↑ nutrient demand → fibrovascular proliferation (Stage 3) → retinal detachment (Stages 4–5)

List the serious complications of ROP.

• Neovascular invasion of vitreous (vessels grow toward vitreous)

• Vitreoretinal adhesions

• Vitreoretinal hemorrhage

• retinal detachment