Surface ectoderm

Lacrimal gland (and drainage system)
Conjunctiva
Corneal epithelium and Bowman’s
Lens
Eyelids, including Meibomian glands and lashes

Mesenchyme (descriptive term for cells between the surface and neuro-ectoderms)

Cranial neural crest

Corneal stroma
Corneal endothelium and Descemet’s
Ciliary body stroma
Ciliary muscleIris stroma
Sclera (outer fibrous condensation)
Choroid (inner vascular condensation)
Trabecular meshwork
Ciliary, otic, pterygopalatine and submandibular ganglion
Sensory ganglia of V, VII, IX and X
Orbital bones and cartilage
Ocular and orbital blood vessels: muscular, connective tissue, endothelial linings

Mesoderm

Hyaloid system/primary vitreous
?Extraocular muscles (thought to derived from “preotic” presumptive myocytes)

Neuroectoderm (neural tube)

Ciliary epitheliumIris epitheliumIris muscles: sphincter and dilator (unique)
Retina (thickened inner layer of vesicle)
RPE (thinner outer layer of vesicle)
Optic nerve, axons and glia

## Embryonic development (first 8 weeks)

Eye development is thought to commence around day 22-23
The eye develops (like the brain) from the most anterior region of the neural plate

Day 22: neural tube forms from closure of the neural folds
Day 23: optic pits first appear
Optic sulci appear in the inner neural plate before the closure of the neural tube
The eye primordium cells express “eye field transcription factors” (EFTFs)

The primordial eye field is initially a single area that later splits under the influence of sonic hedgehog (Shh) and Six3. Disruption of this process leads to cyclopia
Mutations in the RAX and SOX2 genes are associated with anophthalmia

Optic sulci evaginate to form hollow diverticulae: optic vesicles
The primary vitreous forms around the 5th week

At day 25, the optic vesicles enlarge and are surrounded by mesenchymal cells

Mesenchyme is derived from a mixture of neural crest and mesodermal cells
Optic vesicles are fully formed

Day 27

Localised thickening of the surface ectoderm is visible as the lens placode
A disk-shaped thickening of the neural ectoderm lies beneath this and represents the retinal disk (future neural retina)
Lens placode formation coincides with constriction of the optic vesicle at its attachment to form the optic stalk. Through this, the cavity of the vesicle is continuous with the future third ventricle
NB: the lens placodes role in stimulating progress in ocular development is known as induction

The lens placode and thickened retinal disc invaginate into the optic vesicle (mediated by fibronectin-1 which is regulated by the PAX6 gene (paired-box), as example of an EFTF) to form the bilayered optic cup

Growth of the cup is deficient at the distal and ventral aspects, forming the choroidal fissure
Haploinsufficiency of PAX-6 leads to aniridia and microphthalmia. Homozygous loss leads to anophthalmia
PAX-3 mutations are associated with Klein-Waardenburg syndrome

Day 29: invagination complete
Day 33: optic/embryonic fissure closes
Day 36 (start of week 6): lens vesicle separates from the overlying surface ectoderm

The lens cavity is closed over by epithelial cells and is surrounded by a basal lamina which becomes the lens capsule
Vascular mesenchyme and the hyaloid artery become incorporated into the choroidal fissure to access the lentoretinal space
Edges of the choroidal fissure meet and fuse, incarcerating the hyaloid vessels within, which will form the future central retinal artery and vein
The fissure fuses first at its mid-portion and then proceeds proximally and distally (to the margins of the future pupil)
The final diameter of the cornea is determined by the diameter of the optic cup

Day 39: the first of three waves of mesenchyme passes beneath the surface ectoderm of the optic cup

The first wave lies most posteriorly and forms the corneal endothelium
Subsequent waves form the corneal stroma, iris stroma and iridocorneal angle

Day 51 (week 8: the final week of the embryonic period):

Retina can be distinguished as a thinner outer layer (RPE) and thicker inner neural layer, separated by the almost obliterated cavity of the optic vesicle
NB: Melanin is visible in the RPE from week 5
The lens cavity is obliterated by forming primary lens fibres
Mesenchyme condenses around the optic cup

The loose inner layer is highly vascularised: choroid (homologous with the pia and arachnoid mater around the brain)
Outer layer forms the sclera, homologous with the dura

Ganglion cells axons develop from the inner retina to the optic stalk to form the future optic nerve
Secondary lens fibres begin developing
Secondary vitreous develops

At this stage the eye is 1.5-2.0cm long

Gestational age	Embryonic length
Day 22	2 mm
Day 27	5 mm
Day 29	7 mm
Day 37	9 mm
Day 44	15 mm

## Primitive ophthalmic artery

Dorsal:

Becomes the definitive ophthalmic artery
Temporal long posterior ciliary artery
Short posterior ciliary arteries
Central retinal artery

Ventral

Almost disappears
Remnant forms the nasal long posterior ciliary artery

Vascularisation of the nasal retina occurs before the temporal retina (shorter distance from the optic disc to the nasal ora serrata)

## Infant eye

Poor pupil dilatation due to underdeveloped dilator pupillae
Normal AL: 16mm
Shallow AC compared to adults
Normal corneal diameter: 10mm
Foveal maturation is completed postnatally within the first few months

Increased cone density
Macular differentiation is not complete until 4-6 months after birth
Ganglion cel nuclei directly overlie the fovea and are gradually displaced peripherally

Primary fixation reflex:

Foveal fixation with either eye
Present at birth
Eye movements are grossly conjugate and may diverge (rarely converge)

Preference for patterns over plain objects can be seen at birth
Conjugate fixation reflex:

Ability to move the eyes together during versions
Develops from 2-3 weeks of age

Fix and follow (with head movements):

Develops from 6-8 weeks

Smooth pursuit and accommodation develop from 2 months
Convergence develops by 6 months
Lacrimal gland secretion of tears: 1 month post-natal
Colour sense: develops in the second year

## Myelination of the optic nerve

Myelination starts at the chiasm and progresses towards the lamina cribrosa
Myelination of the optic nerve itself commences at 7-8 months gestation
Continues up until 1 year after birth
Proceeds from the brain towards the eye
Stops at the lamina cribrosa

Summary of ocular embryogenesis

First trimester	First month
		Day 22	Optic groove appears
		Day 23	Optic pit forms
		Day 25	Optic vesicle forms
		Day 26	Early extraocular muscles form (except lateral rectus and superior oblique)
		Day 27	Lens placode forms Lateral rectus appears
		Day 28	Choroidal fissure forms Future RPE pigments
		Day 29	Superior oblique appears
	Second month
		Week 5	Hyaloid vessels and primary vitreous appears Lens vesicle forms Orbital bones develop
		Week 6	Choroidal fissure closes Secondary vitreous develops (secreted by retina) Primary lens fibres develop Ciliary ganglion appears Vasculature develops
		Week 7	Ganglion cells migrate to disc Choroidal vessels develop Waves of neural crest for corneal and TM endothelium, then corneal stroma, then iris stroma Tunica vasculosa lentis Sclera appears
		Week 8	Lacrimal gland
	Third month		Rods and cones differentiate Ciliary body develops AC visible Sclera condenses Maximum number of optic nerve axons at this stage and decreases thereafter
Second trimester	Fourth month		Retinal vasculature Hyaloid vessels start to regress Lamina cribrosa forms Iris sphincter Ciliary muscle (longitudinal) Tertiary vitreous (secreted by ciliary body) Bowman’s layer (the last corneal layer) Schlemm’s canal Eyelid glands and cilia Major arterial circle of iris
	Fifth month		Photoreceptors differentiate Eyelid separation
	Sixth month		Cones differentiate (continue to develop post-natally) Ganglion cells thicken at maculaIris dilator Nasolacrimal patency (the distal portion is the last to open)
Third trimester	Seventh month		Rods differentiate Ora serrata Choroidal pigmentation Ciliary muscle (circular) Optic nerve myelination Orbicularis Peripheral displacement of the ganglion cells forms fovea
	Eighth month		Hyaloid vessels disappear
	Ninth month		Retinal vessels reach the periphery Pupillary membrane disappears
Post-natal
	At birth		Foveal fixation Single layer of ganglion cells at fovea
	2-3 weeks		Conjugate fixation
	1 month		Lacrimal gland secretion
	2 months		Smooth pursuit Accommodation
	4 months		No ganglion cells at fovea
	6 months		Convergence
	2 years		Colour vision