DEVELOPMENT OF THE EYE
by Victoria Ort, Ph.D and David Howard, M.D.
II. Development of the Optic Cup and Lens Vesicle
III. Development of the Retina
IV. Development of the Lens
V. Development of the Choroid, Sclera and Cornea
VI. Development of the Iris and Ciliary Body
VII. Vitreous Body
VIII. Eyelid and Conjunctiva
IX. Extraocular Muscles
XI. Congenital Abnormalities of the Eyes
TABLE 1 – DERIVATIVES OF VARIOUS LAYERS
1. To understand the structure and development of the eye.
2. To understand the major congenital malformations.
The major development of the eye takes place between week 3 and week 10 and involves ectoderm, neural crest cells, and mesenchyme. The neural tube ectoderm gives rise to the retina, the iris and ciliary body epithelia, the optic nerve, the smooth muscles of the iris, and some of the vitreous humor. Surface ectoderm gives rise to the lens, the conjunctival and corneal epithelia, the eyelids, and the lacrimal apparatus. The remaining ocular structures form from mesenchyme.
On or about day 22, two small grooves develop on each side of the developing forebrain in the neural folds. They are called optic grooves, or optic sulci. (Fig. 17.1/19.1). As the neural tube closes, these grooves become outpocketings and are now called optic vesicles. The optic vesicles extend from the forebrain toward the surface ectoderm through the adjacent mesenchyme. As the optic vesicles grow toward the ectoderm, their connections to the forebrain become attenuated to form optic stalks, which will eventually become the optic nerves.
The portion of each optic vesicle that interacts with the surface ectoderm induces that area of the ectoderm to form a thickening called the lens placode (a precursor of the lens). The lens placode invaginates to become a lens pit, which soon forms a complete circle that pinches off from the surface ectoderm to become the lens vesicle. At the same time the lens vesicle is forming, the optic vesicle also invaginates to form a double-layered structure called the optic cup. So at this point we see a goblet-shaped optic cup with the lens vesicle floating in its open end (Fig. 17.2/19.2).
The developing optic vesicle and stalk have a groove on their inferior surfaces called the optic, or choroidal, fissure, through which blood vessels gain access to the optic cup as well as the lens vesicle. The blood vessels are the hyaloid artery, a branch of the ophthalmic artery, and its accompanying vein. The choroidal fissure will eventually fuse, completing the eye wall inferiorly and enclosing the vessels in a canal in the optic stalk. When the lens matures later on in fetal life, the distal end of the hyaloid artery will disintegrate and its proximal end will persist as the central retinal artery.
The two layers of the optic cup will further differentiate into the retina of the mature eye.
The two layers are unequal in size - the outer one is thinner than the inner one. The optic cup can be divided into two portions, the anterior 1/5 (rim) and the posterior 4/5. The rim area will ultimately form the iris and ciliary body, and the posterior 4/5 will form the retina (Figure 1). The outer layer of the posterior 4/5 will become the pigment layer of the retina, and the inner one will become the neural retina. These two layers are separated by the intraretinal space (Fig. 17.3/19.3).
The development of the retinaıs pigment layer is very straightforward, with the appearance of melanin granules in the cells of this layer at around 4 1/2 weeks. Slightly later, at about 6 weeks, the cells in the posterior aspect of the inner layer of the optic cup begin a more complicated process. The cells immediately adjacent to the intraretinal space begin to differentiate into the photoreceptors (rods and cones). The next layer of cells will become the Muller supporting cells and the bipolar neurons, and the innermost superficial layer will develop into the axons of the ganglion cells, the ones that will make up the optic nerve. This means light actually passes through the neuronal layers before reaching the rods and cones. The ganglion cell fibers gradually fill in the lumen of the optic stalk as it becomes the optic nerve. By eight months, all the layers of the retina that you will see in your Histology course are recognizable. But maturation of the photoreceptors continues after birth, which in part explains why a babyıs visual acuity improves as he or she grows.
At about the same time as the pigmented layer of the retina is developing, the cells of the posterior part of the lens vesicle transform into elongated, slender primary lens fibers. These new cells fill in the previously hollow structure. About four weeks later, more lens fibers develop, this time from the anterior wall of the lens vesicle (secondary lens fibers).
During the sixth and seventh weeks the mesenchyme that surrounds the external surface of the optic cup condenses into two layers, an inner, pigmented, vascular layer known as the choroid and an outer, fibrous layer called the sclera. The mesenchyme that is anterior to the developing lens splits into two layers that surround the newly formed anterior chamber of the eye (Fig. 17.7/19.6). The inner layer is continuous with the choroid and is called the iridopupillary membrane and the outer layer is continuous with the sclera. The outer layer will form the substantia propria, or stroma of the cornea. The cornea has three layers, epithelium, stroma, and endothelium. The external corneal epithelium develops from surface ectoderm and the endothelium forms from neural crest cells that migrate from the rim of the optic cup. As mentioned above, the stroma is derived from the surrounding mesenchyme. The iridopupillary membrane eventually disappears completely, which allows communication between the anterior and posterior eye chambers.
The anterior rim of the optic cup gives rise to the epithelium of the iris and the ciliary body. Remember that the inner layer of the posterior 4/5 of the optic cup forms the neural retina of the eye. The anterior part of this inner layer forms the non-pigmented layer of the iris and the ciliary process epithelium. The outer layer of the optic cup in this region contributes the pigmented epithelial layer. A few folds form in the anterior aspect of the optic cup and this forms the ciliary processes (Fig. 17.6/19.5). The stroma of the iris and the ciliary body develop from neural crest cells that migrate into the area. Within the stroma of the iris, the sphincter pupillae and dilator pupillae muscles develop from optic cup neuroectoderm. In contrast, the ciliary muscle, which is responsible for changing the shape of the lens, is derived from overlying mesenchyme. The color of the eye is determined by the amount of melanin distributed in the stroma of the iris. Eyes of all colors have melanin in the epthelium on the posterior aspect of the iris.
The vitreous body forms in the center of the optic cup posterior to the lens. It is comprised of a gel-like substance called vitreous humor derived from mesenchymal cells of neural crest origin. Later on more vitreous humor is added which is believed to come from the neuroectoderm of the optic cup.
The eyelids begin to form in the sixth week from neural crest cells as well as surface ectoderm just anterior to the cornea. They begin as two folds of skin that meet over the cornea and they are attached to one another until about the 27th week when they separate. While they are adherent to one another there is a conjunctival sac between the eyelids and the cornea (Fig. 17.719.6). The orbicularis oculi, which is found within the eyelids, forms from the second branchial arch along with the other muscles of facial expression and will be innervated with SVE fibers.
The extraocular muscles develop from three preotic somites. These are the somites founds anterior to the developing ear of the embryo. Each preotic somite is supplied by its own cranial nerve. Remember three different cranial nerves (III, IV, and VI) supply the extraocular muscles. So the somite which is supplied by the III cranial nerve forms 5 of the 7 extraocular muscles while the remaining two each give rise to one muscle each.
X. Regulation of Eye Development
Normal development of the eye requires a rather complex interplay between different tissues of the eye and involves several reciprocal inductive events (Fig. 2). The PAX6 gene product, a transcription factor, is a key player in the process. Development of the eye begins with the designation of a single eye field in the neural plate before neurulation begins. The separation of this single eyefield into two eyefields is dependent upon secretion of sonic hedgehog (shh) from the prechordal plate. It has been suggested that the sonic hedgehog protein suppresses the expression of the PAX6 gene and upregulates the PAX2 gene in the anterior neural ridge, which causes the field to divide in two (Fig. 19.8). A defect in the sonic hedgehog protein or its expression, therefore, results in cyclopia (See Face and Pharyngeal Arches chapter).
In the third week when the optic vesicle buds from the neuroectoderm, it induces the overlying surface ectoderm to form the lens placode by secreting the growth factor BMP4. The ability of the surface ectoderm to respond to BMP4 is dependent on the expression of the PAX6 gene in the surface ectoderm. The lens placode in turn becomes the inducer and secretes growth factors (FGF among them) that induce the optic vesicle to differentiate into the optic cup. Then as the lens vesicle forms from the lens placode it secretes factors that induce the formation of the neural retina in the wall of the optic cup. In addition, the lens vesicle also induces the overlying ectoderm to begin forming the cornea. Now the neural retina becomes the inducer and secretes factors that cause the cells at the inner aspect of the lens vesicle to elongate and become lens fibers. As the inner neural retinal layer is forming, the mesenchyme surrounding the optic cup secretes transforming growth factor (TGF), which induces the formation of the pigmented retinal layer as well as the choroid and the sclera.
1. Coloboma (Fig. 17.11/19.10) This is a condition in which the choroid fissure does not completely close as it should in the seventh week and therefore there is a defect in the inferior part of the iris which gives a keyhole appearance to the pupil. Sometimes the defect can include the retina as well which can compromise vision. Coloboma can be caused by environmental factors or it can be transmitted as an autosomal dominant gene.
2. Congenital Glaucoma Since glaucoma is a result of the abnormally high intraocular pressure, congenital glaucoma can be caused by abnormal development of the iridocorneal angle structures that are responsible for the proper drainage of fluid. This can be caused by a rubella infection or by recessive mutant genes.
3. Congenital Cataracts In this condition the lens is opaque and often looks white. This is due to improper growth of the lens fibers. Again it can be caused by a rubella infection in the mother, depending on the timing - if the infection occurs after the lens has developed then the cataracts do not form. It is important for this anomaly to be corrected within the first year of life otherwise the further development of the retina will not take place because proper connections between the optic nerve and the brain cannot be established.
4. Congenital Detached Retina This occurs when the intraretinal space persists. Recall that this is the space between the pigment epithelium and the light sensitive portion of the retina. Although the pigment layer is strongly attached to the underlying choroid layer, there is never a strong attachment between the two layers of the retina which is why a severe blow to the head can also cause a non-congenital detached retina.
5. Partially Persistent Iridopupillary Membrane (Fig. 17.11/19.10) This occurs when the iridopupillary membrane that covers the lens for a brief period in utero does not dissolve. If so, web-like strands of tissue can be seen over the pupil in newborns. It is asymptomatic.
6. Persistent Hyaloid Artery As mentioned earlier, the hyaloid artery initially supplies both the lens and the retina. Then the distal part of this vessel disappears and the proximal portion becomes the central artery of the retina. When the distal end does not disappear completely there is impairment of vision and possibly hemorrhages into the eye.
7. Microphthalmia As the name suggests this the presence of an unusually small eye. It may be associated with other ocular defects. Usually the side of the face that is affected is underdeveloped. Although the eye is small, vision can be quite good. Some kind of cosmetic surgery is usually performed. A common cause of this condition is infection by rubella virus, HIV and herpes simplex virus. Some drugs can also cause it.
8. Peterıs Anomaly This condition is due to a persistent lens stalk. This means that the lens vesicle does not pinch off from the surface ectoderm and therefore a fairly normal looking eye develops except for a white mass where the undersurface of the cornea is connected to the anterior aspect of the lens by a stalk. This occurs in about 1:10000 people. It has been linked to mutations in the gene encoding pax6, a homeobox transcription factor important for lens formation.
2. Corneal epithelium
3. Conjunctiva and caruncle
4. Eyelid skin
5. Lacrimal apparatus (glands and drainage system)
Head mesenchyme (neural crest and/or mesoderm)
1. Blood vessels
2. Corneal stroma and endothelium
3. Stroma of choroid, ciliary body, and iris
4. Ciliary muscle
6. Optic nerve sheath (meninges)
7. Extraocular muscles and fasciae
8. Remainder of the eyelids (orbicularis oculi muscle, tarsus, orbital septum, etc)
9. Vitreous (part)
What is the embryonic tissue origin (i.e., ectoderm, neuroectoderm from neural tube, head mesenchyme, etc.) of the following: optic cup, optic stalk, optic nerve, rods and cones, pigmented epithelium, lens, cornea, sclera, choroid, extra-ocular muscles, hyaloid artery, conjunctiva.
Where are the rods and cones located within the retinal cell layers? How do they end up there (consider the original optic cup and the change in position it undergoes)?
Where are the blood vessels of the retina and how did they reach there?
Which tissues in the eye act as inducers for other tissues?
What are the following abnormalities and what are their embryonic origins?