EMBRYOLOGY

OF THE EYE
(OCULAR DEVELOPMENT)

ANN MARIE TABUCAN-ISAGA, MD

 EMBRYOGENESIS
• Two (2) weeks after fertilization, the impregnated
ovum undergoes a series of repeated cell divisions
and, through repositioning and reorientation of the
cells, becomes sequentially…
- Morula
- Blastula
- Gastrula
• Only a small number of cells of the inner cell mass
derived from the fertilized ovum, subsequently
differentiates into the embryo.

• The outer cell mass (trophoblast) forms the placenta

and support tissues.

• The epiblast and hypoblast formation from the inner

cell mass precedes gastrulation resulting in the
establishment of the 3 primary germ layers:
ectoderm, mesoderm, and endoderm.
• Cells of the epiblast in the medial region of the
embryonic disk begin to proliferate at the
caudal end, which causes the development of a
thickening known as the primitive streak.

- The cells migrate both laterally

and cephalad beneath the
epiblast giving rise to the
mesenchymal cells of the
intraembryonic mesoderm.

• The remaining cells of the epiblast are now

recognized as the embryonic ectoderm.
• Some cells of the primitive streak invade the
hypoblast and laterally displace most of these cells
giving rise to the embryonic endoderm.

• The primitive streak elongates by the addition of cells

at the caudal end, thus establishes embryo’s axial
orientation.

• The cranial end of the primitive streak enlarges as

the primitive node. Mesenchymal cells that migrate
cranially from this site form the medial notochordal
process, which develops into the primitive
mesenchymal axial skeleton (notochord) of the
embryo.
• The development of the notochord induces the
overlying ectoderm to differentiate into
neuralectoderm that becomes identified as the
neural plate.

The brain and the

eye develop from
the most anterior
region of the
neural plate.
• Growth of the lateral part of the neural plate results
in folds that develop upward and outward, parallel
to the neural groove from the head to the caudal
region.

• At this stage, neuroectoderm lines the inner folds,

and surface ectoderm covers the outer surface of
the folds.

• The neuroectodermal cells at the apex of the folds

proliferate and produce a population of neural crest
cells, which contribute extensively to the tissue of the
eye.
• The cephalic neural folds grow and
expand markedly.

• At the end of the 3rd week after conception, the

neural folds begin to close to form the neural tube.
This process starts in the midregion of the embryo
and proceeds anteriorly and posteriorly at the same
time.

• As the neural tube closes, 3 important events in the

eye and orbit development occurs simultaneously…
•3 important events in the eye and orbit
development:

1. Optic pits develop from the optic sulci, small

depressions present in the cephalic
neuroectoderm.
2. Neural crest cells begin migration.
3. As the anterior neural tube closes, it flexes
ventrally.
 ORGANOGENESIS
(CHRONOLOGY OF EMBRYONIC & FETAL DEVELOPMENT)

22 days Optic primordium appears in neural folds.

25 days Optic vesicle evaginates. Neural crest cells migrate
to surround vesicle.
28 days Vesicle induces lens placode.
2nd month Invagination of optic and lens vesicles.
Hyaloid artery fills embryonic fissure.
Closure of embryonic fissure begins.
Pigment granules appear in the RPE.
Primordia of LR and SO muscles grow anteriorly.
Eyelid folds appear.
 (CHRONOLOGY OF EMBRYONIC & FETAL DEVELOPMENT)

2nd month Retinal differentiation begins with nuclear and

marginal zones.
Migration of retinal cells begins.
Neural crest cells of corneal endothelium migrate
centrally. Corneal stroma follows.
Cavity of lens vesicle is obliterated.
Secondary vitreous surrounds hyaloid system.
Choroidal vasculature develops.
Axons from ganglion cells migrate to optic nerve.
Glial laminal cribrosa forms.
Bruch’s membrane appears.
 (CHRONOLOGY OF EMBRYONIC & FETAL DEVELOPMENT)

3rd month Precursors of rods and cones differentiate.

Anterior rim of optic vesicle grows forward, and
ciliary body starts to develop.
Sclera condenses.
Vortex veins pierces sclera.
Eyelid folds meet and fuse.
4th month Retinal vessels grow into NFL near optic disc.
Folds of ciliary processes appear.
Iris sphincter develops.
Descemet’s membrane forms.
Schlemm’s canal appears.
 (CHRONOLOGY OF EMBRYONIC & FETAL DEVELOPMENT)

4th month Hyaloid system starts to regress.

Glands and cilia develop.
5th month Photoreceptors develop inner segments.
Choroidal vessels form layers.
Iris stroma is vascularized.
Eyelids begin to separate.
6th month Ganglion cells thicken in macula.
Recurrent arterial branches join the choroidal vessles.
Dilator muscle of iris form.
7th month Outer segments of photoreceptors differentiate.
Central fovea starts to thin.
 (CHRONOLOGY OF EMBRYONIC & FETAL DEVELOPMENT)

7th month Fibrous lamina cribrosa forms.

Choroidal melanocytes produce pigment.
Circular muscle forms in ciliary body.
8th month Chamber angle completes formation.
Hyaloid system disappears.
9th month Retinal vessels reach the periphery.
Myelination of fibers of optic nerve is complete to
lamina cribrosa.
Pupillary membrane disappears.
 ORGANOGENESIS
• The Optic sulci are first recognizable as slight, curved
indentations in the widest part of each neural fold just
internal to the peak of the ridge.

• The Optic pits, formed of a single layer of

neuroectoderm, develop from the continued
evagination of the sulci. As the neural tube closes, the
pits deepen and become optic vesicles, which appear
as symmetrical, hallow, hemispherical outgrowths on the
lateral sides of what is now the forebrain vesicle.
 ORGANOGENESIS
• The Optic vesicles remain attached to, and continuous
with, the neural tube by optic stalks composed of
neuroectodermal cells.

• As the optic vesicle approaches the outer wall of the

embryo, a focal thickening of the cells, the Lens
placode, develops in the surface ectoderm.

• At 4th week, the invagination og the lens placode leads

to formation of the Lens vesicle, which initially remains
attached to the surface ectoderm by the lens stalk.
 ORGANOGENESIS
• Simultaneous differential growth and movement of
the cells of the optic vesicle result in the invagination
of its temporal and lower walls and the formation of
the Optic cup.

• The outer layer of the optic cup will evolve as a

monolayer of cells, the RPE. The inner invaginated
layer will differentiate into the neurosensory retina.
 Neurosensory Retina
• Neurosensory/Neural retina arises from the inner layer of
neuroectodermal cells of the optic cup.

• Differentiation of the retina begins in the center of the

optic cup and gradually extends peripherally towards its
rim.

• The ganglion cells are the first cells of the retina to

become clearly differentiated. The number of this cells
increases rapidly between 15 and 17 AOG, then
decreases between 18 and 30 because of apoptosis.
 Neurosensory Retina
• Photoreceptors arise from the outermost layer of
neuroblast cells. Mitotic activity is abundant in 4-12
weeks in the outer neuroblastic layers, and ceases in
the central retina by 15 weeks AOG.
 Fovea
• Differentiation of the neurons, photoreceptors, and glial
cells in the fovea occurs early because this region is the
focal point for the centraperipheral development of the
retina.

• Thinning of the ganglion cells and inner nuclear layers

begins at 24-26 weeks AOG and gives rise to the earliest
recognizable depression in the area of the macula

• Foveal pit becomes more prominent by the 7th month as

a result of the marked thinning o the inner nuclear layer.
 Retinal Pigment Epithelium (RPE)
• Differentiation of the RPE begins at the posterior pole
and proceeds anteriorly, so by 8 weeks AOG the RPE
is organized as a single layer of hexagonal columnar
cells located posteriorly. The cells become tall and
cuboidal during the 3rd and 4th months, and the
terminal web becomes well established at the
lateral apical borders. And RPE is thought to be fully
functional at this stage.

• The basement of the RPE becomes the inner portion

of Bruch’s membrane, the outer layer is laid doen by
the choriocapillaries layer.
 Optic Nerve
• The optic cup is connected to the brain by the optic
stalk, which has a groove, the choroidal fissure, on its
ventral surface.
In this groove are the hyaloid vessels.

• The nerve fibers of the retina returning to the brain lie

among cells of the inner wall of the stalk.

• During the 7th week the choroid fissure closes, and a

narrow tunnel forms inside the optic stalk.
 Optic Nerve
• The optic stalk is transformed into the optic nerve.
• Its center contains a portion of the hyaloid artery,
later called the central artery of the retina.

• On the outside a continuation of the choroid and

sclera, the pia arachnoid and dura layer of the
nerve, respectively, surround the optic nerve.
 Lens
• One of the earliest events in the embryogenesis is
determination of the lens development.

• The lens is first apparent at about 27 days’ AOG as a

disk-shaped thickening of surface epithelial cells
over the optic vesicle. But it becomes ellipsoid with
the addition of secondary fibers which makes the
sutures become more complex and dendriform.

• The equatorial diameter of the unfixed human lens

measures 2mm at 12 weeks and 6mm at 35 weeks.
 Vitreous
• Between the 4th and 5th weeks AOG, the space
between the lens vesicle and the inner layer of the
optic cup becomes filled with fibrils, mesenchymal
cells, and vascular channels of the hyaloid system
which constitute the primary vitreous.

• The development of the secondary vitreous begins

soon after the primary vitreous is established. It is
avascular and consists of type II collagen fibrils and
hyalocytes.
 Vitreous
• Between the 3rd and 4th months AOG, collagen fibrils
of the secondary vitreous condense and become
attached to the internal limiting membrane at the
rim of the optic cup.

• The condensation of fibrils extends to the lens

equator and constitutes the tertiary vitreous.
 Choroid
• Its development begins at the anterior region of the
optic cup and proceeds posteriorly toward the optic
stalk.

• The development is associated with the

condensation of neural crest cells around the cup
that differentiate into cells of the choroidal stroma.

• Choroidal stromal is demarcated by the sclera at

the end of the 3rd month AOG.
 Choroid
• Melanosomes appear between 24 and 27 weeks
AOG, most notably in the melanocytes of the outer
choroid and suprachoroid.

• Melanocytes differentiates from neural crest cells.

• Melanogenesis proceeds anteriorly from the optic

disc to the ora serrata.

• A few immature melanosomes can be found in the

choroidal melanocytes at birth.
 Cornea
• The separation of the lens vesicle from the surface
ectoderm initiates the development of the cornea.

• At 5-6 weeks AOG, the cornea consists of the

following:
• a superficial squamous and a basal cuboidal layer of
epithelial cells
• a primary stroma
• A double layer of endothelial cells posteriorly
 Cornea
• The diameter of the unfixed cornea measures…
- 2mm at 12 weeks AOG
- 4.5mm at 17 weeks AOG
- 9.3mm at 35 weeks AOG
 Sclera
• The sclera is formed by mesenchymal cells that
condense around the optic cup. Most of these cells
are derived from the neural crest.

• It is developed anteriorly before the 7th weeks AOG

and gradually extends posteriorly.
Anterior Chamber, Angle, Iris, and Ciliary Body
• The anterior chamber is first recognizable as the
slitlike space that results after the ingrowth of the first
wave of mesenchymal cells and the posterior
extension of the second wave.

• By 7 weeks AOG, the angle of the anterior chamber

will develop into the trabecular meshwork.

• By the end of 3rd month AOG, Schlemm’s canal

develops from a small plexus of venous canaliculi.
Anterior Chamber, Angle, Iris, and Ciliary Body
• The dilator muscle is not apparent until the 6th
month, and differentiation of the myoepithelial cells
continues at birth.

• The iris is still immature at birth.

 Vascular System
• Vascular channels from the internal carotid artery
develop in the mesenchyme around the optic vesicle
late in the 4th week AOG.

• The hyaloid artery is a branch of the primitive dorsal

ophthalmic artery that arises at the juncture of the optic
stalk and the optic cup at the time of closure of the
embryonic fissure.

• The primitive dorsal ophthalmic artery becomes the

definitive ophthalmic artery of the orbit at 6th week AOG.
 Vascular System
• The primitive dorsal ophthalmic artery supplies the
temporal long posterior ciliary artery, the short
posterior ciliary arteries, and the central retinal artery.

• The primitive ventral ophthalmic artery almost

disappears; only a portion remains as the long
posterior nasal ciliary artery.

• At the 4th month AOG, spindle-shaped mesenchymal

cells arise from the hyaloid artery at the optic disc.
These cells infiltrate the inner layers of the retina.
 Vascular System
• Retinal vascularization proceeds centripetally, and a
boundary zone consisting of undifferentiated cells
distinguishes the avascular and vascular retina.

• Vascularization of the nasal retina is complete before

that of the temporal retina because of the shorter
distance from the optic disc to the nasal ora serrata.

• By 5th month AOG, patent vessels have extended

superiorly and inferiorly on the temporal aspect of the
retina, sparing the region of the macula.
 Vascular System
• By 6th month AOG, small blood vessels begin to
develop in the ganglion cell layer of the foveal slope.

• By 8th month AOG, capillaries reach the ora serrata.

• The mature pattern of vascularization is not achieved

until 3 months after birth.
 Periocular Tissues and Eyelids
• By 4th week AOG, the frontonasal and maxillary
processes of neural crest cells occupy the space that
surrounds the optic cups. The bones, cartilage, fat
and connective tissues of the orbit develop from
these cells.

• All bones of the orbit are membranous except the

sphenoid, which is initially cartilaginous.

• Ossification begins during the 3rd month AOG, and

fusion occurs between the 6th and 7th months AOG.
 Periocular Tissues and Eyelids
• The EOM were once thought to begin developing at
the primitive muscle cone that surrounds the optic
nerve in the 5th week AOG, recent evidence suggests
that the muscles arise in situ.

• The upper eyelid first develops as a proliferation of

surface ectoderm in the region of the future outer
canthus at 4-5 weeks AOG. During the 2nd month,
both the upper and lower eyelids are discernible.

• Margins of the eyelid folds fuse by 10th weeks AOG.

 Periocular Tissues and Eyelids
• The lacrimal gland begins to develop between 6th
and 7th weeks AOG.

• Ducts of the gland are formed at 3 months AOG.

• Lacrimal gland (reflex) tear production does not

begin until 20 or more days after birth. Hence,
newborn infants cry without tears.
 Realignment of the Globe
• Initially, the axes of the 2 optic cups and the optic
stalks form an angle of 180°. At 3 months AOG, this
angle has decreased to 105°.

• With continued enlargement, remodeling and repositioning

of the head, face and brain throughout gestation, the eyes
become oriented in their anterior position.

• At birth, the axes form an angle of 71°. However, the adult

orientation of 68° is not achieved until the age of 3 years.
 DERIVATIVES OF EMBRYONIC TISSUES

ECTODERM
Neuroectoderm
Neurosensory retina
Retinal pigment epithelium
Pigmented ciliary epithelium
Nonpigmented ciliary epithelium
Pigmented iris epithelium
Sphincter and dilator muscle of iris
Optic nerve, axons, and glia
Vitreous
 DERIVATIVES OF EMBRYONIC TISSUES

ECTODERM
Cranial Neural Crest Cells
Corneal stroma and endothelium
Sclera
Trabecular meshwork
Sheathe and tendons of extraocular muscles
Connective tissues of iris
Ciliary muscles
Choroidal stroma
Melanocytes (uveal and epithelial)
 DERIVATIVES OF EMBRYONIC TISSUES

ECTODERM
Cranial Neural Crest Cells (continuation…)
Schwann cells of ciliary nerves
Ciliary ganglion
All midline and inferior orbital bones, as well as parts of
orbital roof and lateral rim
Cartilage
Connective tissue of orbit
Muscular layer and connective tissue sheaths of all
ocular and orbital vessels
 DERIVATIVES OF EMBRYONIC TISSUES

ECTODERM
Surface Ectoderm
Epithelium, glands, cilia of skin of eyelids and caruncle
Conjunctival epithelium
Lens
Lacrimal gland
Lacrimal drainage system
Vitreous
 DERIVATIVES OF EMBRYONIC TISSUES

MESODERM
Fibers of extraocular muscles
Endothelial lining of all oprbital and ocular blood vessels
Temporal portion of sclera
Vitreous
 MOLECULAR REGULATION
• PAX6 is the master gene for the eye development.
• Initially, this transcription factor is expressed in a
band in the anterior neural ridge of the neural plate
before neurulation begins.

• At this stage, there is a single eye field that later

separates into two optic primordia.
• The signal for separation of this field is sonic
hedgehog (SHH) expressed in the precordal plate.
 MOLECULAR REGULATION
• The SHH expression up-regulates PAX2 in the center
of the eye field and down-regulates PAX6.

• Later this pattern is maintained so that PAX2 is

expressed in the optic stalks and PAX6 is expressed in
the optic cup and overlying surface ectoderm that
forms the lens.

• Once the lens induction occurs, bone

morphogenesis protein 7 (BMP7), a member of the
TGF-b GF gene family, is necessary to maintain eye
development.
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