Formation of Optic Primordia

Broadly speaking, the embryonic and fetal development of the eye occurs in three stages:

It is assumed that the embryonic development of the eye is similar in sequence for all mammalian species and that interspecies differences pertain mostly to the duration of gestation and the age of the various anatomic end points—for example, regression of embryonic vasculature or eyelid opening.

The optic primordia (rudimentary eye) develops from that portion of the embryo that later forms the anterior part of the central nervous system (CNS). The first step in the embryogenesis of the future eye takes place at the embryonic plate stage, when the ectoderm invaginates along the posterior-anterior axis to form the neural groove. The two neural lips of the groove subsequently fuse, thus turning the groove into the neural tube (Figures 2-1 and 2-2). At the site of fusion, between the ectoderm and the neuroepithelium (the epithelium of the neural tube), neuroepithelial cells proliferate to form the neural crest cells and migrate sideways into the paraxial and lateral mesoderm. These neural crest cells mix with mesodermal cells and form the secondary mesenchyme; this secondary mesenchyme forms the main mesodermal structures of the eye. Therefore the eye develops from the neural ectoderm, neural crest, and surface ectoderm, with minor contributions from the mesoderm.

Figure 2-1 Developing embryo at the start of neural tube formation.

(From Yanoff M, Duker J [2004]: Ophthalmology, 2nd ed. Mosby, St. Louis.)

Figure 2-2 Formation of neural tube. A, Dorsal surface of embryo as seen from above. B, Vertical section through three-layered embryonic disc. C, Neural groove forms in neural plate area of ectoderm. D, Neural groove invaginates and neural folds are formed. E, Neural folds continue to grow toward each other. F, Neural crest cells separate from ectoderm of neural folds as the folds fuse; neural tube is formed (of neural ectoderm); and surface ectoderm is again continuous. G, Evaginations in area of forebrain form the optic pits.

(From Remington LA [2005]: Clinical Anatomy of the Visual System, 2nd ed. Butterworth-Heinemann, St. Louis.)

The anterior end of the neural tube enlarges and bends down to form the primordia of the CNS. On its outer surface, on both sides, appear two small pits called the optic grooves or optic pits. These pits, which appear on day 13 of gestation in the dog, are the anlage of the eyes (see Figure 2-2, G).

With the closure of the anterior end of the neural tube, intratubular fluid accumulates and its pressure causes the evagination of the optic grooves and their transformation into the two optic vesicles (Figures 2-3 and 2-4). This marks the beginning of organogenesis. In the dog this event occurs on the fifteenth day of gestation. The lumen of the neural tube remains connected to the cavities of the optic vesicles by two optic stalks (see Figure 2-4, D). Under the pressure of the intratubular (intraventricular) fluid, the optic vesicles continue to enlarge and bulge, eventually coming in contact with the surface ectoderm. At the site of contact with the optic vesicle the surface ectoderm thickens and forms the lens placode (Figures 2-3; 2-4, C; and 2-5). The contact of the optic vesicle with the surface ectoderm serves as an induction for the optic vesicle to start invaginating, thus forming the double-layered optic cup (see Figures 2-3 and 2-4, E and F).

Figure 2-3 Formation of the optic vesicle, optic cup, and lens vesicle.

(From Yanoff M, Duker J [2004]: Ophthalmology, 2nd ed. Mosby, St. Louis.)

Figure 2-4 Early eye development. A, Dorsal view of the cranial end of 22-day embryo, showing the first indication of eye development. B, Transverse section through neural fold, showing an optic groove. C, Forebrain and its covering layers of mesenchyme and the surface ectoderm from an embryo of about 28 days. D, F, and H, Sections of the developing eye, illustrating early stage in the development of the optic cup and lens vesicle. E, Lateral view of the brain of an embryo at about 32 days, showing the external appearance of the optic cup. G, Transverse section through the optic stalk, showing the optic fissure and its contents.

(From Remington LA [2005]: Clinical Anatomy of the Visual System, 2nd ed. Butterworth-Heinemann, St. Louis.)

Figure 2-5 Light micrograph of 6-mm pig embryo showing thickening of lens placode.

(From Remington LA [2005]: Clinical Anatomy of the Visual System, 2nd ed. Butterworth-Heinemann, St. Louis.)

The invagination of the vesicle progresses from inferior to superior but is not completed on the ventral side of the optic cup, where a fissure, called the embryonic optic fissure, remains. The double layers of the optic cup are aligned on both sides of the fissure, which extends posteriorly under the optic stalk. This fissure allows the secondary mesenchyme present around the cup to penetrate into the cavity of the optic cup to form the hyaloid vascular system (twenty-fifth day of gestation in the dog) (see Figure 2-4, G and H). This fissure gradually closes leaving a small aperture at the anterior end of the optic stalk, through which the hyaloid artery passes (Figure 2-6). The hyaloid artery supplies the inner layers of the optic cup and developing lens vesicle. The two lips of the optic fissure fuse anteriorly to the optic stalk. The fusion process progresses anteriorly and posteriorly, eventually causing closure of the optic cup and allowing intraocular pressure to build up (see Figure 2-6).

Figure 2-6 Closure of optic fissure. A and C, Views of inferior surface of optic cup and stalk, showing progressive stages in closure of optic fissure. B and D, Transverse sections through optic stalk, showing successive stages in closure of optic fissure. Note that the lumen of optic stalk is obliterated gradually.

(From Remington LA [2005]: Clinical Anatomy of the Visual System, 2nd ed. Butterworth-Heinemann, St. Louis.)

The lens placode thickens to become the lens vesicle. Following the invagination of the optic vesicle, the lens vesicle finds itself embedded inside the cavity of the cup (see Figure 2-4, F and H). Anteriorly, the hyaloid artery gives branches, the tunica vasculosa lentis, which cover the posterior and lateral faces of the lens. This vascular network supplies the metabolic requirements of the lens during development. The hyaloid vascular system disappears at advanced stages of the development or during the postnatal period. In dogs remnants of the hyaloid system might remain visible until the fourth postnatal month, whereas in cattle they may persist until 12 months of age. In humans, but not in domestic animals, the caudal portions of the hyaloid artery and vein transform themselves into the central retinal artery and vein.

At this stage of development, organogenesis has been completed and the general structure of the eye has been determined. It is followed by a period of differentiation as the specific structures of the eye begin to form. Their development is reviewed in the following sections, beginning with the posterior parts of the eye and progressing anteriorly.

Retina

The optic cup is lined by two layers of epithelium of neuroectodermal origin (see Figure 2-4, H). The inner layer, facing the vitreous, is nonpigmented, but the outer layer, facing the (future) sclera, is pigmented. The anterior rim of the cup will form the anterior uvea (ciliary body and iris), and the posterior part of the cup will form the retina. The two epithelial layers of the optic cup will form the two epithelial layers of the retina and the anterior uvea.

The outer epithelial layer of the posterior optic cup forms the pigment epithelium of the retina. The inner epithelial layer forms the sensory retina (Figure 2-7). The two layers of the posterior optic cup are separated by the intraretinal space representing the cavity of the optic vesicle, which has gradually been obliterated during the invagination of the optic vesicle. Diseases of the posterior segment of the eye cause retinal detachment in this space as the sensory retina separates from the pigment epithelium.

Figure 2-7 The two retinal walls. The inner retinal wall shows two zones—an inner, nonnucleated layer and a deeper, nucleated layer.

(From Yanoff M, Duker J [2004]: Ophthalmology, 2nd ed. Mosby, St. Louis.)

The common neuroblastic layer, which is the nuclear portion of the sensory retina, divides into an outer neuroblastic layer and an inner neuroblastic layer (see Figure 2-7). These outer and inner neuroblastic layers are separated by the fiber layer of Chievitz. The cells of the outer neuroblastic layer differentiate into cones and rods externally and horizontal cells internally. The cells of the inner neuroblastic layer differentiate into ganglion cells, amacrine cells, bipolar cells, and Müller’s cells. The rods and cones (i.e., the photoreceptors) form the outer retina and are adjacent to the choroid and sclera (Figure 2-8). The ganglion cell layer, which originated in the inner neuroblastic layer, is called the inner retina because it is adjacent to the vitreous. The resulting retina is called an inverted retina because the photoreceptors are close to the outer layers of the eye and light must pass through all of the retinal layers to reach the photoreceptors. The reason for this arrangement is to place the photoreceptors next to the choroid, thus giving these cells, which have very high metabolic requirements, their own “private” blood supply.

Figure 2-8 Photomicrographs of the posterior section of the eye. A, The three posterior layers of the eye. The sclera is the outermost layer, whereas the retina faces the vitreous. B, An enlargement of the 10 layers of the retina. The retinal pigment epithelium and the photoreceptors are the outermost layer of the retina, facing the choroid. The ganglion cell layer and nerve fiber layer are the innermost layers of the retina, facing the vitreous.

(From Remington LA [2005]: Clinical Anatomy of the Visual System, 2nd ed. Butterworth-Heinemann, St Louis.)

There is species variation in the degree of retinal development present at birth. In dogs it is possible to record electrophysiologic activity of the photoreceptors during the first postnatal week; signals reach adult amplitude by 5 to 8 weeks of age. Similarly, differentiation of the rod and cone inner and outer segments is evident histologically during the first 8 weeks of life.

Optic Nerve

Axons from the ganglion cells grow toward the optic stalk, thus forming the nerve fiber layer, the innermost layer of the retina (see Figures 2-6, B and D; and 2-8). Axons from throughout the entire retina converge on the optic disc, where they form into bundles collectively known as the optic nerve (cranial nerve II) (Figure 2-9). The axons of optic nerve extend posteriorly to form the optic chiasm and optic tracts before making their first synapse at the lateral geniculate nucleus.

Figure 2-9 Formation of optic nerve. A, Axons of ganglion cells of the retina grow through optic stalk to brain. B, Transverse section through the optic stalk, showing the formation of the optic nerve. The optic nerve is formed after closure of the optic fissure (this stage follows the stage shown in Figure 2-6, C). C, The lumen of the optic stalk is obliterated as axons of ganglion cells accumulate in the inner layer of the stalk.

(From Remington LA [2005]: Clinical Anatomy of the Visual System, 2nd ed. Butterworth-Heinemann, St. Louis.)

As the ganglion cell axons collect at the optic disc they displace primitive neuroectodermal cells forward, into the vitreous cavity. These displaced cells form a glial sheath around the hyaloid artery. At the disc, the same cells may form an agglomeration called Bergmeister’s papilla, which protrudes into the vitreous. The papilla may persist into adult life (especially in ruminants), or it may atrophy, thus forming a depression, known as the physiologic optic cup, in the optic disc (Figure 2-10). In newborns this physiologic optic cup may be confused with a coloboma of the optic disc. In patients with glaucoma the physiologic optic cup may enlarge owing to the forces of the increased intraocular pressure on this region of the eye.

Figure 2-10 Optic nerve heads of a dog (A) and a sheep (B). The dark spot in the center of the canine optic nerve head is the physiologic optic cup (arrow). The pink tuft in the center of the sheep optic nerve head is the ovine Bergmeister’s papilla (arrow).

(Courtesy University of California, Davis, Veterinary Ophthalmology Service Collection.)

Vitreous

The embryonic vitreous consists of the primary, secondary, and tertiary vitreous (Figure 2-11). The primary vitreous develops with the hyaloid vasculature (Figure 2-12). It has mesenchymal, neuroectodermal, and ectodermal components. The mesenchymal elements enter posteriorly with the hyaloid vessels, and anteriorly through the space between the anterior rim of the optic cup and the lens vesicle. The ectodermal elements are the fibrils produced by the posterior face of the lens. The primary vitreous also contains neuroectodermal elements, which consist of the fibrils produced by the inner limiting membrane of the retina. The secondary vitreous is the “definitive” vitreous that will persist into adulthood. It is denser, is more homogeneous and avascular, and is laid down around the primary vitreous (see Figures 2-11, B, and 2-13). It is also secreted by the inner limiting membrane of the retina. The tertiary vitreous is secreted by the ciliary epithelium. Bundles of fibers extend from the ciliary epithelium toward the lens equator, covering the secondary vitreous anteriorly (see Figure 2-11, C). In the adult they persist as lens zonules (suspensory ligament of the lens).

Figure 2-11 Scheme of main features in vitreous development and regression of hyaloid system, shown in drawings of sagittal sections. A, Hyaloid vessels and branches occupy much of the space between lens and neural ectoderm, forming the primary vitreous. B, An avascular secondary vitreous of fine fibrillar composition fills the posterior part of the eye. The primary vitreous shown in A is condensed into Cloquet’s canal as the hyaloid vessels atrophy. C, Vessels of hyaloid system atrophy progressively. Zonular fibers (tertiary vitreous) begin to stretch from growing ciliary region toward lens capsule.

(Modified from Duke-Elder S [editor] [1963]: System of Ophthalmology. Vol III: Normal and Abnormal Development, Part 1. Embryology. Henry Kimpton, London.)

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