Prenatal Development of the Eye and Its Adnexa
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Prenatal Development of the Eye and Its AdnexaCYNTHIA S. COOK, VICTORIA OZANICS and FREDERICK A.
JAKOBIEC
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EARLY MORPHOGENESISLENS INDUCTION AND DIFFERENTIATION
CONNECTIVE TISSUE COATSSTRUCTURES OF THE AQUEOUS OUTFLOW PATHWAYS
UVEA
NEUROECTODERMAL LAYERSBRUCH'S MEMBRANE
OPTIC NERVE AND DISC
VITREOUS AND HYALOID SYSTEM
ADNEXACONCLUSIONS
ACKNOWLEDGMENTSREFERENCES
In this text, we attempt to provide an overview of ocular embryology bydescribing essential developmental events in a concise fashion. Fine
structural data on human and primate eye components have become available
since the appearance of standard publications on ocular embryology byMann,
1Barber,
2Dejean and coworkers,
3and Duke-Elder and associates.
41
These observations aid in reconfirming or reevaluating the functional
development of ocular structures as expressed by morphologic changes. Our
descriptions are based on mammalian tissues, including both humans andother species that serve to model human development. Comparisons have
demonstrated that the sequence of developmental events is similar across
species. Factors that must be taken into consideration when makinginterspecies comparisons include: duration of gestation; differences in
anatomic endpoint (such as the absence in other species of a macula,
Schlemm's canal, or Bowman's membrane); and when eyelid fusion breaks(during the sixth month of gestation in the human versus 2 weeks postnatally
in the mouse. Within the limits of these species variation, mice have proven
to be a valuable model in the study of normal and abnormal ocular
morphogenesis. In particular, the study of effects of acute exposure to
teratogens during development has provided valuable information about thespecific timing of events leading to malformations.
In development of the eye, as in other organs, the multiplication of cells as
well as directional change in shape, structure, and function of the cells
govern growth. Gene determination decides the direction in which a changecan occur, whereas the reciprocal demands of the individual cells or parts
determine how far that direction must be followed. Fundamentally, the
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process consists of these two activities: change in structure and shape due to
relatively different rates of growth and also change in structure and function
due to differentiation and functional specialization.
Induction of one ocular tissue by another and interrelations between these
developing tissues have been extensively reinvestigated in many laboratoriesusing various experimental techniques.
521One example is the lens, which
arises in direct response to induction by the optic vesicle. The developing
lens, in turn, promotes normal morphogenesis of neural ectodermal andmesenchymal elements in the eye. It has an inducing influence on corneal
differentiation and promotes vitreous growth. Moreover, a strong
organogenetic connection exists between lens and iris. The reciprocal
interactions between optic cup and lens bring about the functional adjustmentof the ocular axes.
Although the neural retina grows and differentiates independently of the
lens, the presence of the lens may influence the normal growth and change inshape of the pigment epithelium, choroid, and sclera. The pigment
epithelium, however, directs the deposition of the mesenchyme around it;
subsequently, all three layers grow in unison. The pigment epithelium alsodepends on the vitreous body for increase in its area.
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EARLY MORPHOGENESIS
Although events occurring during the first few weeks after fertilization, before the appearance of
identifiable ocular primordia, may seem to have little significance to the clinicalophthalmologist, evidence indicates that abnormalities that originate during this period may be
responsible for many ocular malformations that occur in humans.
Gastrulation (formation of the mesodermal germ layer) occurs early in gestation (day 7 in mice,day 20 in humans). The primitive streak forms as a longitudinal groove within the epiblast
(future ectoderm) of the bilaminar embryonic disc. Epiblast cells migrate medially toward theprimitive streak where they invaginate to form the mesodermal layer (Fig. 1). This forms the
classic three germ layers: ectoderm, mesoderm, and endoderm. Gastrulation progresses in a
cranial to caudal direction. Concurrently, cranial surface ectoderm proliferates forming bilateral
elevations called neural folds (Fig. 2). Columnar surface ectoderm in this area now becomes
neural ectoderm.
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Fig. 1. A.Drawing of a 17-day-old embryo in gastrulationstage, dorsal view, with the amnion removed. B.Cross-
section of a 17-day-old embryo through the primitive
streak. The primitive streak represents invagination ofepiblast cells between the epiblast and hypoblast layers.
Note that the epiblast cells filling the middle area formthe mesodermal layer. C.Cross-section of the embryo atthe end of the third week showing the three definitive
germ layers: ectoderm, mesoderm, and endoderm. (Cook CS, Sulik KK, Wright KW:
Embryology. In Wright KW [ed]: Pediatric Ophthalmology and Strabismus, pp 343. St Louis:
Mosby, 1995.
Fig. 2. A.Drawing of dorsal view of a
human embryo at 19 to 20 days'
gestation. The neural plate transforms
into two neural folds on each side ofthe neural groove. The neural groove
in the middle of the embryo isshaded
to represent neural ectoderm; the
unshadedsurface of the embryo issurface ectoderm. B.Cross-section of same embryo through the neural plate. Ectoderm in the
area of the neural groove (shaded cells) has differentiated into neural ectoderm, whereas the
ectoderm on each side of the neural groove is surface ectoderm (clear white cells) (Cook CS,Sulik KK, Wright KW: Embryology. In Wright KW (ed): Pediatric Ophthalmology and
Strabismus pp 343. St Louis: Mosby, 1995.)
Experimental studies in mice using acute exposure to teratogens have demonstrated the
significance of the period of gastrulation to later ocular development. Exposure to ethanol orretinoic acid during a short period equivalent to the third week of human gestation causes
primary damage to the forebrain neural ectoderm.2224
This results in a spectrum ofmalformations including microphthalmia, anterior segment dysgenesis (Peters' anomaly), iris and
optic nerve colobomas, and persistent hyperplastic primary vitreous.25,26
As the neural folds elevate and approach each other (neurulation), a specialized population of
mesenchymal cells, the neural crest, emigrates from the neural ectoderm at its junction with the
surface ectoderm. In the development of the eye, the neural ectoderm(deriving from the neuralplate and neural folds), thesurface ectoderm, the neural crest, and, to a lesser extent, the
mesodermare of importance (Table 1).
TABLE 1. Embryonic Origins of Ocular Tissues
Neural ectoderm (optic cup)
Neural retina
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Retinal pigment epithelium
Pupillary sphincter and dilator muscles
Posterior iris epithelium
Ciliary body epitheliumOptic nerve
Neural crest (connective tissue)
Corneal endotheliumTrabecular meshwork
Stroma of cornea, iris, and ciliary body
Ciliary muscleChoroid and sclera
Perivascular connective tissue and smooth muscle cells
Meninges of optic nerve
Orbital cartilage and boneConnective tissue of the extrinsic ocular muscles
Secondary vitreous
Zonules
Surface ectoderm (epithelium)
Corneal and conjunctival epitheliumLens
Lacrimal gland
Eyelid epidermisEyelid cilia
Epithelium of adnexa glands
Epithelium of nasolacrimal duct
Mesoderm (muscle and vascular endothelium)
Extraocular muscle cells
Vascular endothelia
Schlemm's canal endothelium
Blood
The cranial neural crest contributes most of the connective tissues of the eye and its adnexal
structures.14,19,2741
The hyaluronic acid-rich extracellular matrix influences migration and
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differentiation of the neural crest cells. This acellular matrix is secreted by the surface epithelium
as well as the neural crest cells and forms a space through which crest cells migrate. Fibronectin
secreted by the noncrest cells forms the limits of the mesenchymal migration. Interactions
between the migrating neural crest and the associated mesoderm appear to be essential fornormal crest differentiation. Many congenital malformations of the anterior segment and cornea
probably arise from derangements in the axial migration of ocular neural crest.
Experimental embryologic studies have shown that the mesoderm actually contributes little to
head and neck mesenchyme. The cranial correlates to the paired paraxial somites are called
somitomeres.Seven pairs of cranial somitomeres have been identified in the mouse .33,40,4251
In
the eye, the mesoderm contributes only to the striated extraocular muscles and vascular
endothelia. To these limited primary mesodermal elements come associated neural crest satellite
cells (surrounding the striated muscles) and pericytes (surrounding the vascular endothelium).Circulating blood elements originate from mesoderm. The term mesenchyme broadly refers to
any embryonic connective tissue and should not be confused with mesoderm. With respect to the
head and neck, most of this connective tissue derives from the cranial neural crest, with the
exceptions mentioned.
The optic primordium is a thickened zone in the differentiating central nervous system that forms
the neural folds of the early embryo. Some of the neuroepithelium composing the opticprimordium becomes the future optic cup and stalk; some cells may delaminate to contribute to
the neural crest.27
The optic sulcus or groove arises in the primordium at the time when the
neural folds are still open in the forebrain (8 to 15 somite pairs, approximately 2 to 3.5 mm)(Figs. 3and4A). With enlargement of the sulcus, the optic evaginations and, later, the optic pits
appear in the region of the future forebrain (seeFig. 4B). The portion of the evaginations
adjacent to the midbrain contacts the mesencephalic neural crest cells, which will form the
mesenchymal envelope isolating neural from surface ectoderm (seeFig. 4C).
Fig. 3. Drawing of 23-day-old embryo, dorsal view, showing partial fusion of
the neural folds. Brain vesicles have divided into three regions: forebrain,midbrain, and hindbrain. Facing surfaces of the forebrain are lined with neural
ectoderm (shaded cells), but the most of the embryo is now lined with surface
ectoderm (clear white) because the neural groove has closed. On the inside ofboth forebrain vesicles is the site of the optic sulci. (Cook CS, Sulik KK,
Wright KW: Embryology. In Wright KW [ed]: Pediatric Ophthalmology and
Strabismus, pp 343. St Louis: Mosby, 1995.)
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Fig. 5. A.Drawing of a cross-section through forebrainand optic sulci of 24-day-old embryo. Note that the neural
tube is still open. The optic sulci are lined by neural
ectoderm (shaded cells), while the surface of the forebrainis covered with surface ectoderm (clear white cells). As
the optic sulci (neural ectoderm) evaginate toward thesurface ectoderm (hollow arrows), the edges of the brainvesicles move together to fuse, thus closing the neural
tube (solid arrows). B.Drawing of a cross-section
through a 26-day-old embryo at the level of the optic
vesicle. Note that neural tube is closed, the surfaceectoderm now lines the surface of the forebrain, and the
neural ectoderm is completely internalized. The surface
ectoderm cells overlying the optic vesicles enlarge to
form the early lens placode. (Cook CS, Sulik KK, WrightKW: Embryology. In Wright KW [ed]: Pediatric Ophthalmology and Strabismus, pp 343. St
Louis: Mosby, 1995.)
The optic vesicles become sheathed with cells of neural crest origin27
that, except for a small
region in the center of the bulge, separate them from the surface ectoderm (seeFig. 4E). The
future primordium of the retina is present before closure of the neural tube, when the neuralectoderm is still open to the amniotic cavity. The optic stalk is formed by a constriction of the
area between the vesicles and the future forebrain. At this time, all cells lining the inner surface
of the vesicle's cavity are ciliated, and its outer surface, as well as the inner aspect of the surface
ectoderm overlying it, is covered by a thin basal lamina.
The next event is invagination of the optic vesicles by differential growth and buckling to form
the optic cup (Figs. 6to9). The temporal and lower walls move inward against the upper andposterior walls. This process also involves the optic stalk so that the optic
(choroid/embryonic/retinal) fissure is formed where the two laterally growing edges of the cup
and stalk meet. Mesenchyme (primarily neural crest) penetrates immediately into the cup byfilling up the fissure.
Fig. 6. Drawing of a transection through a 28-day-old embryoshowing invaginating lens placode that is pushing into the optic
vesicle (arrows), thus creating the optic cup. Note the
orientation of the eyes 180 degrees from each other. This is also
illustrated inFigures 9BandC.(Cook CS, Sulik KK, WrightKW: Embryology. In Wright KW [ed]: Pediatric
Ophthalmology and Strabismus, pp 343. St Louis: Mosby,
1995.)
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Fig. 7. Drawing shows formation of the lens vesicle andoptic cup. Note that the optic fissure is present because
the optic cup is not fused inferiorly. Mesenchyme (M)
surrounds the invaginating lens vesicle. Note that theoptic cup and optic stalk are made of neural ectoderm.
(Cook CS, Sulik KK, Wright KW: Embryology. InWright KW [ed]: Pediatric Ophthalmology andStrabismus, pp 343. St Louis: Mosby, 1995.)
Fig. 8. Drawing of cross-section at approximately 5 weeks'gestation through optic cup and optic fissure. The lens vesicle isseparated from the surface ectoderm. Mesenchyme (M)
surrounds the developing lens vesicle and the hyaloid artery is
seen with the optic fissure. See alsoFigure 9F.(Cook CS, Sulik
KK, Wright KW: Embryology. In Wright KW [ed]: PediatricOphthalmology and Strabismus, pp 343. St Louis: Mosby,
1995.)
Fig. 9. Invagination
of the optic cup andlens vesicle. Mouse
embryos areillustrated. A.Embryo of somite
pairs (fifth week in a
human). On external
examination, theinvaginating lensplacode can be seen
(arrow). Note its
position relative tothe maxillary (Mx)
and mandibular (Mn)prominences of the
first visceral arch ( 106). B.Embryo of the same age as inFigure 3A.Frontal fracture through
the lens placode (arrow) illustrates the associated thickening of the surface ectoderm (E).
Mesenchyme (M) of neural crest origin is present adjacent to the lens placode. Distal portion of
the optic vesicle thickens concurrently, as the precursor of the neural retina (NR), whereas theproximal optic vesicle becomes a shorter, cuboidal layer that is the anlage of the retinal
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pigmented epithelium (PE). The cavity of the optic vesicle (V) becomes progressively smaller( 367). C.Epithelium of the lens placode continues to invaginate (L). There is an abrupt
transition between the thicker epithelium of the placode and the adjacent surface ectoderm,
which is not unlike the transition between the future neural retina (NR) and the futurepigmented epithelium (PE). (Periodic acid-Schiff's stain; 443) D.As the lens vesicle enlarges
during the eleventh day, the external opening, or lens pore (arrow), becomes progressivelysmaller. The lens epithelial cells at the posterior pole of the lens elongate to form the primarylens fibers (L). NR, anlage of the neural retina; PE, the anlage of the pigmented epithelium
(now a very short cuboidal layer) ( 300). E.External view of the lens pore (arrow) and its
relationship to the maxillary prominence (Mx)32 somite pairs ( 260). F.Frontal fracture
reveals the optic fissure (*) where the two sides of the invaginating optic cup meet. This formsan opening in the cup allowing access to the hyaloid artery (H), which ramifies around the
invaginating lens vesicle (L). The former cavity of the optic vesicle is obliterated except in the
marginal sinus (S), at the transition between the neural retina (NR) and the pigmented
epithelium. E, surface ectoderm ( 307).
The optic vesicle and optic stalk invaginate through differential growth and infolding. Localapical contraction
52and physiologic cell death
53have been identified during invagination. This
process progresses from inferior to superior so that the sides of the optic cup and stalk meet
inferiorly in the optic fissure. The two lips of the optic fissure meet and initially fuse anterior to
the optic stalk with fusion progressing anteriorly and posteriorly. Failure of normal closure ofthis fissure may result in inferiorly located defects (colobomas) in the iris, choroid, or optic
nerve.
Closure of the optic cup through fusion of the optic fissure allows establishment of intraocular
pressure. Studies have demonstrated that, in the chick, the protein in the embryonic vitreous
humor is derived from plasma proteins entering the eye by diffusion out of permeable vessels in
the anterior segment.54After optic fissure closure, protein content in the vitreous decreases,possibly through dilution by aqueous humor produced by developing ciliary epithelium.
Table 2lists the chronologic sequence of ocular development and comparative body-eye
measurements in relationship to embryonic time intervals.
TABLE TWO. Revised Sequence of Human Ocular Development
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Mont
h
Week(s
)
Day(s
)
CR
Lengt
h
(mm)
Neuroectoderm
al Derivatives
Posterior iris
epithelium,
ciliary body
epithelium,
pupillary
muscles, neural
retina, retinal
pigment
epithelium
(RPE),
secondary
vitreous, and
optic nerve
Neural Crest
Derivatives
Corneal
endothelium,
stroma of
cornea, iris,
and ciliary
body, ciliary
muscle,
trabecular
meshwork,
choroid,
sclera,
secondary
vitreous, and
orbit
Surface
Ectoderm
Derivatives
Corneal
and
conjunctiva
l
epithelium,
lens, eyelid
epidermis,
eyelid cilia
and glands,
lacrimal
gland,
nasolacrim
al duct
Mesoderma
l
Derivatives
Endotheliu
m of
Schlemm's
canal,
vascular
(hyaloid,
tunica
vascula
lentis
(TVL)
endotheliu
m,
extraocular
muscles
1 3 20 12 Neural platethickens
Gastrulation(formation
of
mesoderm)
4 22 23.5 Optic sulci
present in
forebrain
24 23 Neural tube
closed Opticstalk formed
25 34 Optic sulci
converted into
optic vesicles
Mesenchyme
surrounds optic
vesicle
27 45 Optic vesicle
contacts surface
ectoderm
Lens
placode
begins to
thicken
Eyelidterritory
determined
2 5 29 57 Optic vesicle
begins toinvaginate
forming optic
cup with opticfissure
Lens pit
forms aslens placode
invaginates
Cord ofectoderm
Hyaloid
artery entersthrough the
optic fissure
-
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buried by
maxillaryprocesses to
later form
nasolacrima
l duct
33 79 Optic fissure
closed Pigment
in outer layer ofoptic cup (future
RPE)
Oculomotor
nerve presentTrochlear and
abducens nerves
appear
Lens pit
closed
forminglens vesicle
surrounded
by intact
basementmembrane
(lens
capsule)Corneal
epithelium
formed
6 37 811 Ciliary ganglionpresent
Choriocapillarisformed around
the optic cup
Primarylens fibers
fill lens
vesicle
formingembryonal
nucleus
40 11
14
Retina consists
of: externallimiting
membrane (with
zonulaadherens),
proliferative
zone, primitive
zone, marginalzone, and
internal limiting
membrane
Corneal
endotheliumformed
Secondary
lens fibersform Lid
folds
present
7 4245
1317
Retina consistsof: inner
neuroblastic
layer, transient
fiber layer of
-
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developmen
t
11 7177
505 Inner plexiform
layer formed
Cilia withindeveloping innersegments
Conjunctiva
l goblet
cells present
1214 78
90
60
80
Outer plexiform
layer separates
horizontal andbipolar nuclei
from
rudimentary
rods and conesSynapses
develop betweenphotoreceptors,ganglion cells,
and bipolar cells
in central retinaFirst indication
of ciliary
processes
Lamina
cribrosa
formationbegins
Marginal
bundle of
Drualt/vitreousbase present
Glands of
Moll,
meibomianglands
present
Rectus
muscle
tendons fusewith sclera
Branches of
ophthalmic
arteryaccompany
hyaloidartery Iridalmajor
arterial
circleformed
4 15 90
100
Orbital axis 105 Ciliary muscle
appears
Glands of
Zeisspresent
16 100
120
Mitosis ceases in
the neural retina
Corneal
endothelium
exhibitszonulae
occludentes
Aqueous humorformation
begins
Regression of
corneal
endotheliumcovering
iridocornealangle recess
Schlemm's
canal
presentTunica
vasculosa
lentis beginsto atrophy
120
130
Pupillary
sphincter
develops
Scleral spur
developing
Bowman's
Short
eyelashes
appear
Hyaloid
artery
begins to
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membrane
present
atrophy to
the disc;branches of
the central
retinal artery
form
5 120
180
Outer segments
formation begins
Differentiationof macula begins
Layers of the
choroid
completeCloquet's canal
formed
6 175
230
Pupillary dilator
muscle develops
Ora serratadistinct nasally
Pupillary
membrane
begins toatrophy axially
Capsulohyaloidal ligamentpresent
Eyelids
begin to
open, lightperception
7 220
260
Iris
pigmentation
present Laminacribrosa mature
Myelination
begins at the
chiasm andprogresses to
the lamina
cribrosa
8 240280
Retinal layersdeveloped
except at macula
Regression ofpupillary
membrane
nearly complete
Retinalvessels
reach the
ora serrata
9term
310350
Orbital axis 71 Lacrimalduct
canalized
Back to Top
LENS INDUCTION AND DIFFERENTIATION
As the optic vesicles enlarges, it contacts the overlying surface ectoderm.The first manifestation of lens induction is the appearance of a disc-shaped
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thickening of surface epithelial cells (27 days' gestation) (seeFigs. 5B,6,and
9AandB). A tight, extracellular matrix-mediated adhesion between the optic
vesicle and the surface ectoderm has been described. This anchoring effect
on the mitotically active ectoderm results in cell crowding and elongationand formation of a thickened placode. Adhesion between the optic vesicle
and lens placode serves to ensure alignment of the lens and retina in thevisual axis. Although adhesion between the optic vesicle and surfaceectoderm exists, the respective basement membranes remain separate and
intact throughout the contact period (seeFig. 4F). Inductors for lens
formation may act on the regulation of structural genes, or they may actdirectly on the cell cytoplasm. Lens induction thus may involve transfer of
inductor substances from the optic cup to the surface cells across both
basement membranes. Invagination of the lens placode (29 days) is
accomplished by a synergistic elongation of the placode cells withcontraction of their apical cytoplasm and terminal bar system (seeFigs. 7
and9C). The processes of differentiation into a lens pit, cup, and then a
vesicle have been studied in detail.6171
As the lens placode invaginates, it forms a hollow vesicle (seeFigs. 8and
9D). The area of contact of the optic vesicle and the surface ectodermdetermines the size of the lens vesicle, orbit, and palpebral fissure. The lens
separates from the surface epithelium at about 33 days' gestation (7 to 9 mm;
see Fig. 9D). The vesicle consists of a single layer of cells, covered by abasal lamina. Through appositional growth to its epithelial surface, the basal
lamina acquires more layers that become the lens capsule. At first, the
posterior capsule is more prominent than the anterior; the outer layers may
have components from the mesodermal tissues forming the hyaloid vascular
network.72
A zone of necrosis develops, displacing the lens placode from thesurface ectoderm (seeFig. 9EandF). The process of lens vesicle detachment
is accompanied by active migration of epithelial cells out of thekeratolenticular stalk, cellular necrosis, and basement membrane
breakdown.73,74
Cup formation is achieved by contraction of the apical
filaments. The process of induction is thus localized.
PRIMARY LENS FIBERS
The hollow lens vesicle consists of a single layer of epithelial cells with cell
apices directed toward the center. Following detachment from the surface
ectoderm, the lens vesicle is surrounded by a basal lamina, the future lenscapsule. The cells lengthen (Figs. 10and11A)until the lumen of the vesicleis filled (45 days, 17 mm). These constitute the primary lens fibers. The
apical ends of the newly formed fibers become firmly attached to the apical
surface of the anterior lens epithelium.
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Fig. 10. Drawing showing formation ofthe embryonic lens nucleus and primary
lens fibers at approximately 6 weeks.
Neural crest mesenchyme (M) surroundsthe optic cup. The posterior lens
epithelial cells (located nearest thedeveloping retina) elongate to form theprimary lens fibers. The anterior
epithelium remains cuboidal and becomes the anterior epithelium in the
adult. The optic fissure is now closed. The hyaloid vessels are seen between
the lens and retina. (Cook CS, Sulik KK, Wright KW: Embryology. InWright KW [ed]: Pediatric Ophthalmology and Strabismus, pp 343. St
Louis: Mosby, 1995.)
Fig.
11.Form
ation
of the
lensfibers
;
earlyretina
l
differ
entiation.
A.Elon
gation of the lens fibers located nearest to the neural retina forms the
embryonal lens nucleus (L) and obliterates the lens vesicle cavity. The
endothelial cells that form the tunica vasculosa lentis are indicated byarrows ( 392). B.Formation of the secondary lens fibers is apparent as
elongation of the epithelial cells at the equatorial lens bow. C, cornea; NR,
neural retina; L, lens ( 270). C.Electron micrograph evaluation of the
developing lens (L). LE, anterior lens epithelium, E, surface ectoderm (298). D.Corneal endothelium (open arrow) and stroma (C) are completely
formed but the anterior iridial stroma and iridocorneal angle (*) structures
are still immature and covered by the endothelium. The outer, pigmented
layer of the optic cup (O), which forms the pupillary sphincter and dilatormuscles, is in apposition to the cornea in the area of the future aqueous
outflow pathways (*). The arrowhead indicates the capillaries of the
anterior tunica vasculosa lentis. L, lens ( 407). Eand F.The retina hassegregated into an inner neuroblastic layer (IN) containing the primitive
ganglion cells the axons of which form the nerve fiber layer (arrow), and an
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outer neuroblastic layer (ON) containing the primordia of thephotoreceptors, retinal interneurons, and glial cells (E, 430; F, 316).
PE, retinal pigmented epithelium.
The retinal anlage promotes primary lens fiber formation in the adjacent lens
epithelial cells. Surgical rotation of the lens vesicle in the chick's eye by 180
degrees results in elongation of the lens epithelial cells nearest thepresumptive retina, regardless of the orientation of the transplanted lens.
56
The retina thus develops independently from the lens, while the lens appears
to rely on the retina for cytodifferentiation. This transformation of primarylens fibers is accompanied by ultrastructural changes in the nucleus and
cytoplasm, decreased numbers of organelles, and increased numbers of
fibrillar materials composed of the characteristic lens proteins.71
The
primitive lens filled with primary lens fibers forms the embryonal nucleus,visible in the adult. This portion of the lens lacks sutures.
SECONDARY LENS FIBERS
The cells nearest the corneal primordium remain cuboidal and become the
lens epithelium, which remains mitotic throughout life, giving rise to futurelens fiber cells. Production of the secondary lens fibers is initiated by
migration of the anterior epithelial cells toward the equator and their
elongation at various degrees with a shift in their nuclear distribution, thusresulting in the lens bow (Fig. 12B,C,andF,and13;seeFigs. 11BandC).
The basal ends of the fibers remain tightly attached to the basal lamina; their
apical ends extend anteriorly to the center, thus forming the anterior suture.
The tips of these secondary fibers are not yet tapered. A corresponding
increase in cell volume and decrease in intercellular space within the lensaccompany lens fiber elongation.
61The lens fibers exhibit surface
interdigitations. They extend around the primary fibers beneath the capsuleand meet in planes, the lens sutures, arranged essentially vertically to the
surface. The basic anatomy of the lens is established after the first layer of
secondary fibers has been placed (seventh week of gestation).75
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Fig.12.
Form
ationof
thelensand
irido
corne
alangle
. A.
Ante
riorsegm
ent at8week
s'
gestation.
The
corne
al stroma (C) and endothelium have formed. The dense pupillary membrane(arrow) fills much of the space within the anterior chamber. L, lens ( 100).
B.Fractured lens at 7 weeks' gestation. Note embryonic nucleus (N) and
anterior lens epithelium (arrow) ( 102). C.Higher magnification of (B) toillustrate secondary lens fibers and lens bow ( 376). D.Longitudinal view
of lens fibers illustrating interdigitations ( 706). E.Cross-section of lens
fibers illustrating tightly apposed hexagonal arrangement ( 1012). F.Light
microscopic view of lens bow and close proximity of lens equator withanterior margin of optic cup. Note the hyaloid vasculature surrounding the
lens (arrows) ( 220). G.At 8 weeks' gestation, following removal of the
lens and the pupillary membrane, the anterior chamber can be visualized (103). H.Higher magnification of (G). The edge of the pupillary membrane
can be seen (arrow) as well as the anterior margin of the optic cup (O) and
the developing outflow pathways. The clefts visible in the limbal region
canalize to form Schlemm's canal. C, cornea ( 220). I.At 13 weeks'gestation, there are immature ciliary processes located in the region of the
future posterior iris (arrow). Differential growth with relative posterior
movement of the inner optic cup, results in the ultimate matureconformations coinciding with exposure of the trabecular meshwork as
described by Anderson ( 95). C, cornea; (B-E,courtesy of Dr. Kathy
Sulik.)
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Fig. 13. Lens at 65 mm (12-week fetus) intransverse section. Posterior suture (arrow) extends
from the surface to the central, primary lens fibers
(location of the embryonic nucleus). The triangularanterior suture (thick arrow) is indicated by an
assembly of transversely cut fibers at the anteriorpole. Posterior vascular lens capsule is indicated byhollow arrow. The nucleated area is the location of
the secondary lens fibers. Lens bow (Lb) is formed by anteriorly migrating
nuclei of newly formed lens fibers. pm, vessels of the pupillary membrane;
V, vitreous ( 40).
LENS SUTURES
Succeeding generations of cells extend anteriorly and posteriorly from the
equator beneath the capsule. The anterior suture line is shaped like a Y that is
inverted in the posterior aspect. The posterior suture is formed when theposterior central cells lose their nuclei, become separated from their basal
lamina, and migrate inward.66
Curved lens fibers result, with the superficial
ones being the longest. Linear and triradiate sutures form, representingdifferent stages in lens development.
MATURATION
The shape of the lens and its orientation with respect to the optic axis
continually adjust to the developing eye. This is partly regulated by theneural retina and peripheral mesenchyme.
10Through the third month of
gestation, the anteroposterior diameter is greater than the equatorial. Mainlybecause of the continued generation of secondary fibers, the equatorialdiameter increases rapidly, thus making the lens more and more ellipsoid.
The lens, still somewhat spherical at birth, grows throughout life.
A general structural densification occurs progressively during maturation.
Fibrillar material is increased within the cytoplasm and cell organelles are
decreased. The successive parallel layers of interdigitating, elongated lensfibers become tightly apposed (seeFig. 12DandE). Deeper nuclei become
homogenous and dense. By the end of the third month, the innermost cells
have lost their nuclei and simultaneously show disintegration of the
chromatin and the ribosomes, leaving a finely filamentous cytoplasm.
Back to Top
CONNECTIVE TISSUE COATS
CORNEA
Among the many publications on the morphogenesis of the cornea (Fig. 14)
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and the development of its constituents in various vertebrates, only a few can
be cited in this general review.
Fig.
14.
Schema
tic
diag
ramof
the
dev
eloping corneacentral region. A.At 39 days, the two-layered epitheliumrests on a basal lamina. It is separated from a two-to three-layered
endothelium by a narrow, cellular space. B.At 7 weeks, mesenchyme
from the periphery migrates into the space between epithelium andendothelium. It is the precursor of the future corneal stroma. C.The
mesenchyme (fibroblasts) is arranged in four to five incomplete layers by
7 weeks and a few collagen fibrils appear among them. D.By 3 months,the epithelium has 2 to 3 layers of cells and the stroma about 25 to 30 layers
of fibroblasts (keratoblasts) that are more regularly arranged in its posterior
half. There is a thin, uneven Descemet's membrane between the most
posterior keratoblasts and the monolayered endothelium. E.By midterm(4.5 months) some wing cells are forming above the basal epithelial cells
and an indefinite, acellular Bowman's membrane emerges beneath the basal
lamina. About one third of the anterior portion of the multilayered stroma
has its keratoblasts ina disorganized formation. Descemet's membrane iswell developed. F.At 7 months the cornea has its adult structure
established. A few mostly superficial keratoblasts are still randomly
oriented with respect to the corneal surface. The collagenous lamellae in therest of the stroma are in parallel array with only a few spaces in the matrix
lacking collagen fibrils. Breaks (near the bottom of Eand F) indicate that
the central portion of the stroma is not represented.
Epithelium
When the lens cup separates from the surface ectoderm in embryos at about
33 days' postfertilization (7 to 9 mm in length), development of the corneacan be said to have begun. The surface ectoderm becomes continuous
covering the optic cup and lens vesicle and later develops into the cornealepithelium.
Descemet's Membrane and Endothelium
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During the next week, mesenchymal cells grow centrally between the basal
laminae of the lens and corneal epithelium (Fig. 15;see14A-C). Posterior to
the basal lamina of the corneal epithelium, the mesenchyme has produced a
double row of flattened cells, the future corneal endothelium (seeFig. 14A).
Fig. 15. Corneal epithelium (Ep) andmesenchymal cells (Me) beneath the
basal lamina are destined to form the
endothelium. Section is from a
monkey embryo at 34 days,comparable with that of a human at
approximately 5.5 weeks ( 480). Le,
lens.
Descemet's membrane first appears at 8 weeks as a patchy accumulationresembling basement membrane material.
91,92The patches become confluent
and thickened owing to the synthetic activity of the endothelial cells.Evidence of organization is seen early during the fourth month, when four or
five superimposed lamellae interspersed with collagen fibrils appear on the
stromal side of the endothelial basal lamina. The endothelium has zonulaeoccludentes at the cell apices by the middle of the fourth month of
development. Their appearance corresponds to the onset of aqueous humor
formation.
Stroma
Following formation of the corneal endothelium, mesenchyme (neural crest)
continues to migrate axially over the rim of the optic cup during the seventhweek (17 to 18 mm) (Fig. 16). At 8 weeks (18 to 22 mm), migratingmesenchymal cells from the periphery invade the space between epithelium
and endothelium. This mesenchyme, as well as that which will give rise to
the sclera and iris stroma, is of neural crest origin.30
The central portion ofthe future stroma is still acellular (seeFig. 14B). The endothelium merges
with the stratified cells at the periphery over the lips of the optic cup. This
mass of cells, in turn, is continuous with the cellular scleral condensation
extending to the equator of the globe. The developing keratocytes begin to
produce glycosaminoglycans.104
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Fig. 16. Embryo at 22 mm (approximately 7 weeks)showing relation of the anterior segment components (
260). The two arrowsindicate blood channels in the
mesenchyme around the rim of the cup. Peripheral part ofthe pupillary membrane running from the mesenchyme in
front of the optic cup (mes) to the anterior lens capsuleoutlines the incipient anterior chamber lying between itand the posterior surface of the cornea (hollow arrows).
Asterisk is placed at the peripheral limit of the anterior chamber. Curved
arrows point to capsula perilenticularis fibrosa. C, cornea; LE, lens
epithelium; V, primary vitreous; ov, tip of the neuroectodermal optic cup.
In the early 8-week-old embryo, about 22 mm in length, the mesenchymal
stroma consists centrally of five to eight rows of cells (Fig. 14C), within afibrillar matrix containing collagen. Nerves have been identified within the
corneal stroma and between epithelial cells at 3 months.105107
The most posterior layers of the corneal stroma are confluent peripherally
with a condensed band of mesenchyme that is gradually spreading backward
to enclose the eye. The mesenchyme destined to form the sclera is notdistinct from that which will form the four oculomotor muscles.
The cornea at 2 months (about 20 mm) consists of an epithelium of outersquamous and basal columnar cells. The middle polygonal or wing cells of
the adult do not appear until the fourth or fifth month. The stroma has about
15 layers of cells with rapidly developing collagen fibrils, most in the
posterior portion. At 3 months, the endothelium of the central area consists
of a single row of flattened cells that seem to rest on an interrupted basallamina, the first indication of a thin Descemet's membrane. With the
exception of Bowman's membrane, all corneal components are present (seeFig. 14D).
Bowman's Membrane
Arising relatively late in gestation (seeFig. 14EandF), Bowman'smembrane is observed by light microscopy during the fifth month, but
somewhat earlier by electron microscopy. It is always acellular, presumably
formed by the most anterior fibroblasts of the stroma, which move
posteriorly as Bowman's fibers and the ground substance are synthesize. Theepithelium may play a partial role in the local polymerization of the collagen
precursors presumably produced by the most anterior stromal fibroblasts.108
Transparency
Perhaps the most important and unique corneal characteristic is its
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transparency, which also develops during fetal life. The early embryonic and
fetal cornea is translucent rather than transparent and is more hydrated than
in the adult.94
Condensation begins in the posterior stroma during fetal
maturation.95
At about the time that the most anterior stromal lamellae areformed, corneal transparency reaches adult quality. During this development,
the water content of the cornea is being reduced so that the adult level ofcorneal hydration is attained at the same time as transparency.
SCLERA
The sclera forms first anteriorly, by mesenchymal condensation at the limbus
near the future insertion of the rectus muscles and grows gradually
posteriorly. Fibrocytes are involved in the synthesis of the elastic foci in thesclera.
109In contrast, the cornea lacks elastic components.
Inspection of the sclera at 60 to 65 mm or 12 weeks reveals it as a
mesenchymal condensation that has reached the posterior pole of the eye andsurrounds the optic nerve. Some cells have entered among the optic nerve
fibers and are arranged transversely, forming the first stages of theconnective tissue lamina cribrosa. The scleral spur appears at 4 months as
circularly oriented fibers; at 5 months, it is visible behind the anterior
chamber. At this time the sclera is well differentiated all around the eye.
Although the corneal and scleral cells are derived from the same mass of
mesenchyme surrounding the anterior part of the optic cup, they behavedifferently when in their definitive position. Corneal fibroblasts form
collagen faster than the scleral cells and differ in the rate and amount of
noncollagenous protein that they synthesize.110
Back to Top
STRUCTURES OF THE AQUEOUS OUTFLOW PATHWAYS
IRIDOCORNEAL ANGLE
Light and scanning electron-microscopic studies reveal the anterior chamberangle of the human eye to have a continuous endothelial lining during the
third and fourth months (Figs. 17and18). The tissues in the angle later
differentiate into a loose reticulum with large enclosed spaces near the iris
and ciliary body; outside of this trabecular tissue, a tighter aggregation of
cells is oriented toward the sclera.111115With the growth of surroundingstructures, Schlemm's canal comes to lie at the level of the apex of the angle.
Descemet's membrane and the corneal endothelium still cover a portion of
the trabecular meshwork, but the endothelial lining of the chamber hasbecome discontinuous (Figs. 19and20). The loose reticular tissue of the
earlier stages now occurs only in the deepest part of the angle, where it has
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large intercellular spaces (seeFigs. 17Cand20).
Fig. 17. Schematic diagram of theprogressive deepening of the angle;
its relation to the neighboring tissues.
A.At 3 months, corneal endotheliumextends nearly to the angle recess: an
incipient Schlemm's canal
(arrowhead) and a more posterior
scleral spur condensation (hollowarrow) appear to its left. Pigment
epithelium of the forward growing
ectodermal optic is indented by blood
vessels. The secondary vitreous fibrilsrun parallel to its surface (arrow).
This is the faisceau isthmique or
marginal bundle of Druault. B.At 4months, the angle recess has deepened and the endothelial lining has
receded somewhat. There is a small aggregate of differentiating sphincter
muscle fibers near the tip of the optic cup. Arrowhead points to Schlemm'scanal. The condensed tissue just posterior to Schlemm's canal is the
developing scleral spur (hollow arrow). Arrow points to the developing
tertiary vitreous or zonular fibers. They originate from the nonpigmented
ciliary epithelium and pass at right angles through Druault's bundle towardthe lens capsule. C.The iris has grown and only its ciliary portion is
presented. The angle recess has deepened and is occupied by loose
connective tissue separated by many spaces. The dilator muscle of the iris
has reached its root, which is still thick.Arrowheadpoints to the majorarterial circle. D.Sphincter muscle is fully developed and is separated by
connective tissue septa into several groups of cells. The collarette is
represented as a surface stromal bulge containing two blood vessels (curvedhollow arrow). E.Schematic diagram of the developing iris dilator muscle
at 6 months. During the sixth month, dilator muscle fibers (Dil. M) start to
differentiate from extensions of the anterior epithelial cells (AE) into thestroma (ST). These cells are located peripherally to the developing von
Michel's spur (MS), which itself is a pigmented projection of the anteriorepithelium, demarcating the posterior limit of the sphincter muscle (SP). In
the developing dilator muscle, myofilaments within the elongating
processes become arranged parallel to the stromal axis. Someundifferentiated anterior epithelial cells (UN) are present. In the sphincter,
which had originated earlier from the same layer of anterior epithelial cells,
connective tissue septa and a capillary (CA) start to grow between clumpsof cells, but connective tissue has not yet invaded between the muscle cells
and the anterior pigment epithelium beneath it. Eventually, the sphincter
muscle bundles become completely separated from the anterior epithelium,
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whereas the dilator muscle sheet remains as the multilayered stromalprojection of a part of this epithelium never separating from it. Therefore,
the dilator muscle is not a separate cellular layer, but rather a partial myoid
differentiation of cellular processes of the anterior neuroectodermalpigment epithelial cells. P, pupillary margin; PC, posterior chamber; PE,
posterior epithelium; PM, pupillary membrane.
Fig. 18. Excavation of the anterior chamber (AC) angle in
a fetus at 75 mm (3 months) is at a level with the rim ofthe optic cup, which is well ahead of the lens bow. The
corneal endothelium extends to the apex of the angle
(hollow arrow). The location of the future trabecularmeshwork is indicated by the arrow. On the side toward
the lens, the angle is limited by the forward extension of
the loosely woven mesenchyme over the optic cup
margin. Blood vessels in the recesses of the pigment epithelium (solidarrow) precede its infolding. LE, lens epithelium; pm, pupillary membrane.
Fig. 19. Angle at 7 months (approximately
225 mm). Apex of the wedge-shaped
trabecular meshwork (Tr) is not in theillustration. The corneal endothelium (En)
extends over one third of the trabecular
lamellae. The loose tissue in the angle
recess is isolated from the anterior chamber(AC) by processes of the reticular and
mesenchymal cells (hollow arrows). There are large clefts (*), some of
which are confluent, in the angle tissue. The angle recess extends beyond
the level of the middle of the trabecular meshwork, and the immatureSchlemm's canal (circled) is somewhat behind it. Ir, immature iris; Sc,
sclera. (Smelser GK, Ozanics V: The development of the trabecular
meshwork in primate eyes. Am J Ophthalmol 71:366, 1971.)
Fig. 20. The angle in a fetus late in the
ninth month (at approximately 37 weeks)
extends somewhat beyond the posterior
part of the trabecular meshwork, whichhas its apex at the termination of the
corneal endothelium (En). The scleral spur
(arrow) and the canal of Schlemm
(arrowhead) are in front of the angle.Loose tissue in the angle is indicated by the hollow arrow. AC, anterior
chamber; CM, ciliary muscle; cp, ciliary processes; C, cornea; Ir, iris; PC,
posterior chamber; Sc, sclera.
Anterior chamber angle formation seems to occur through a combination ofprocesses. Differential growth of the vascular tunic results in posterior
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