Development of Retina

The retina develops from the walls of the optic cup (Figs. 17-1 and 17-2). In the invaginated optic cup, the deeper, thinner layer becomes the retinal pigment epithelium, whereas the more superficial, thicker layer differentiates into the neural retina. The two retinal layers are separated by an intraretinal space (Figs. 17-1H and 17-4), which is the original cavity of the optic cup. Before birth, this space gradually disappears as the two layers of the retina fuse (Fig. 17-5D). Because the optic cup is an outgrowth of the forebrain, the layers of the optic cup are continuous with the wall of the brain (Fig. 17-1H). Under the influence of the developing lens, the inner layer of the optic cup proliferates to form a thick neuroepithelium (Fig. 17-4). Subsequently, the cells of the inner layer closest to the retinal pigment epithelium differentiate into the neural retina, the light-sensitive region of the retina (Fig. 17-4). This region contains photoreceptors (rods and cones) and the cell bodies of neurons (e.g., ganglion cells). Because the optic vesicle invaginates as it forms the optic cup, the neural retina is “inverted”; that is, light-sensitive parts of the photoreceptor cells are adjacent to the retinal pigment epithelium. As a result, light must pass through the thickest part of the retina before reaching the receptors; however, because the retina is transparent, it does not form a barrier to light.

The axons of the ganglion cells in the superficial layer of the neural retina grow proximally in the wall of the optic stalk to the brain (Fig. 17-3A). The cavity of the optic stalk is gradually obliterated as the axons of the ganglion cells form the optic nerve (Fig. 17-3F). Myelination of the optic nerve fibers begins late in the fetal period and is completed by the 10th week after birth. Molecular studies have shown that the homeobox genes PAX6 and OTX2 regulate retinal differentiation and pigment formation, respectively.

Coloboma of Iris

In infants with coloboma of the iris, a defect in the inferior sector of the iris or the pupillary margin gives the pupil a keyhole appearance (Fig. 17-6). The coloboma may be limited to the iris, or it may extend deeper and involve the ciliary body and retina. A typical coloboma results from failure of closure of the retinal fissure during the sixth week. The defect may be genetically determined, or it may be caused by environmental factors. A simple coloboma of the iris is frequently hereditary and is transmitted as an autosomal dominant characteristic.

Figure 17–6 Coloboma of the left iris. Observe the defect in the inferior part of the iris (at the 6 o’clock position). The defect represents failure of fusion of the retinal fissure.

(Reprinted from Otolaryngologic Clinics of North America 40(1), Guercio J, Martyn L, Congenital malformations of the eye and orbit, 113-140, Copyright 2007, with permission from Elsevier.)

Development of Choroid and Sclera

The mesenchyme surrounding the optic cup differentiates into an inner, vascular layer—the choroid—and an outer, fibrous layer—the sclera (see Figs. 17-5C and 17-7). At the rim of the optic cup, the choroid forms the cores of the ciliary processes, consisting chiefly of capillaries supported by delicate connective tissue.

Figure 17–7 Photomicrograph of a sagittal section of the eye of an embryo (x50) at approximately 56 days. Observe the developing neural retina and the retinal pigment epithelium. Note the large intraretinal space between the two layers of the retina.

(From Moore KL, Persaud TVN, Shiota K: Color Atlas of Clinical Embryology, 2nd ed. Philadelphia, WB Saunders, 2000.)

Development of Ciliary Body

The ciliary body is a wedge-shaped extension of the choroid (Fig. 17-5C and D). Its medial surface projects toward the lens, forming the ciliary processes. The pigmented part of the ciliary epithelium is derived from the outer layer of the optic cup and is continuous with the retinal pigment epithelium. The nonpigmented part of the ciliary epithelium represents the anterior prolongation of the neural retina, in which no neural elements develop. The smooth ciliary muscle, responsible for focusing the lens and the connective tissue in the ciliary body, develop from mesenchyme at the edge of the optic cup between the anterior scleral condensation and the ciliary pigment epithelium.

Development of Iris

The iris develops from the rim of the optic cup, which grows inward and partially covers the lens (Fig. 17-5D). The epithelium of the iris represents both layers of the optic cup; it is continuous with the double-layered epithelium of the ciliary body and with the retinal pigment epithelium and neural retina. The connective tissue framework of the iris is derived from neural crest cells that migrate into the iris. The dilator pupillae and sphincter pupillae muscles of the iris are derived from the neuroectoderm of the optic cup. These smooth muscles result from a transformation of epithelial cells into smooth muscle cells.

Development of Lens

The lens develops from the lens vesicle, a derivative of the surface ectoderm (Fig. 17-1). The anterior wall of the lens vesicle becomes the subcapsular lens epithelium (Fig. 17-5C). The nuclei of the tall columnar cells that form the posterior wall of the lens vesicle undergo dissolution. These cells lengthen considerably to form highly transparent epithelial cells, the primary lens fibers. As these fibers grow, they gradually obliterate the cavity of the lens vesicle (Figs. 17-5A to C). The rim of the lens—the equatorial zone—is located midway between the anterior and the posterior poles of the lens. The cells in the equatorial zone are cuboidal; as they elongate, they lose their nuclei and become secondary lens fibers (Fig. 17-8). These fibers are added to the external sides of the primary lens fibers. Lens formation involves the expression of L-Maf (lens-specific Maf) and other transcription factors in the lens placode and vesicle. The transcription factors Pitx3 and GAT-3 are also essential for the formation of the lens.

Figure 17–8 Photomicrograph of a sagittal section of a portion of the developing eye of an embryo at approximately 56 days. Observe that the lens fibers have elongated and obliterated the cavity of the lens vesicle.

(From Moore KL, Persaud TVN, Shiota K: Color Atlas of Clinical Embryology, 2nd ed. Philadelphia, WB Saunders, 2000.)

Although secondary lens fibers continue to form during adulthood and the lens increases in diameter as a result, the primary lens fibers must last a lifetime. The developing lens is supplied with blood by the distal part of the hyaloid artery (Figs. 17-4 and 17-5); however, it becomes avascular in the fetal period when this part of the artery degenerates (Fig. 17-5D). After this, the lens depends on diffusion from the aqueous humor in the anterior chamber of the eye, which bathes its anterior surface, and from the vitreous humor in other parts. The lens capsule is produced by the anterior lens epithelium. The lens capsule represents a greatly thickened basement membrane and has a lamellar structure. The former site of the hyaloid artery is indicated by the hyaloid canal in the vitreous body (Fig. 17-5D); this canal is usually inconspicuous in the living eye.

The vitreous body forms within the optic cup (Fig. 17-5C). It is composed of vitreous humor, an avascular mass of transparent, gel-like, intercellular substance.

Development of Aqueous Chambers

The anterior chamber of the eye develops from a cleft-like space that forms in the mesenchyme located between the developing lens and the cornea (Fig. 17-5A and B). The posterior chamber of the eye develops from a space that forms in the mesenchyme posterior to the developing iris and anterior to the developing lens (Fig. 17-5D). After the lens is established, it induces the surface ectoderm to develop into the epithelium of the cornea and conjunctiva. When the pupillary membrane disappears and the pupil forms, the anterior and posterior chambers of the eye communicate with each other through the scleral venous sinus. This sinus encircles the anterior chamber and allows aqueous humor to flow from the anterior chamber of the eye to the venous system.

Development of Cornea

The cornea, induced by the lens vesicle, is formed from three sources:

Development of Eyelids

The eyelids develop during the sixth week from the neural crest–derived mesenchyme and from two folds of skin that grow over the cornea (Fig. 17-5B). The eyelids adhere to one another at approximately the 10th week and remain fused until the 26th to 28th weeks (Fig. 17-5C). The palpebral conjunctiva lines the inner surface of the eyelids. The eyelashes and glands in the eyelids are derived from the surface ectoderm (Chapter 18). The connective tissue and tarsal plates develop from mesenchyme in the developing eyelids. The orbicularis oculi muscle is derived from the mesenchyme in the second pharyngeal arch (see Chapter 10).

Development of Lacrimal Glands

The lacrimal glands are derived from a number of solid buds from the surface ectoderm. The buds branch and canalize to form lacrimal excretory ducts and the alveoli of the glands. The lacrimal glands are small at birth and do not function fully until approximately 6 weeks; hence, the newborn infant does not produce tears when crying.

Development of Internal Ears

The internal ears are the first of the three parts of the ear to develop. Early in the fourth week, a thickening of the surface ectoderm—the otic placodes—appears on each side of the embryo at the level of the caudal part of the hindbrain (Fig. 17-9A and B). Inductive influences from the notochord and paraxial mesoderm stimulate the surface ectoderm to form the otic placodes. Fibroblast growth factor 3 (FGF-3) may play a role in this process. Each otic placode soon invaginates and sinks deep to the surface ectoderm into the underlying mesenchyme, forming an otic pit (Fig. 17-9C and D). The edges of the otic pit come together and fuse to form an otic vesicle (Fig. 17-9E to G). The otic vesicle then loses its connection with the surface ectoderm, and a diverticulum grows from the otic vesicle and elongates to form the endolymphatic duct and sac (Fig. 17-10A to E). As the otic vesicle grows, two regions become visible:

Figure 17–9 Early development of the internal ear. A, Dorsal view of a 4-week embryo (at approximately 22 days). B, C, D, and E, Schematic coronal sections, showing successive stages in the development of the otic vesicles.

Figure 17–10 The otic vesicle, showing the development of the membranous and bony labyrinths of the internal ear. A to E, Lateral views, showing successive stages in the development of the otic vesicle into the membranous labyrinth from the fifth to eighth weeks. F to I, Sections through the cochlear duct, showing successive stages in the development of the spiral organ and the perilymphatic space from the eighth to 20th weeks.

Three disc-like diverticula grow out from the utricular part of the primordial membranous labyrinth. The central parts of these diverticula fuse and disappear (Fig. 17-10B to E). The peripheral unfused parts of the diverticula become the semicircular ducts, which are attached to the utricle and are later enclosed in the semicircular canals of the bony labyrinth. Localized dilatations, the ampullae, develop at one end of each semicircular duct (Fig. 17-10E). Specialized receptor areas—cristae ampullares—differentiate in these ampullae as well as in the utricle and saccule.

From the ventral saccular part of the otic vesicle, a tubular diverticulum—the cochlear duct—grows and coils to form the membranous cochlea (Fig. 17-10C to E). A connection of the cochlea with the saccule, the ductus reuniens, soon forms. The spiral organ differentiates from cells in the wall of the cochlear duct (Fig. 17-10F to I). Ganglion cells of the vestibulocochlear nerve (CN VIII) migrate along the coils of the membranous cochlea and form the spiral ganglion. Nerve processes extend from this ganglion to the spiral organ, where they terminate on hair cells. The cells in the spiral ganglion retain their embryonic bipolar condition.

Inductive influences from the otic vesicle stimulate the mesenchyme around the otic vesicle to differentiate into a cartilaginous otic capsule (Fig. 17-10F). The cartilaginous otic capsule later ossifies to form the bony labyrinth of the internal ear. Transforming growth factor β₁ may play a role in modulating epithelial–mesenchymal interaction in the internal ear and directing the formation of the otic capsule. As the membranous labyrinth enlarges, vacuoles appear in the cartilaginous otic capsule that soon coalesce to form the perilymphatic space. As a result, the membranous labyrinth becomes suspended in perilymph (fluid in the perilymphatic space). The perilymphatic space related to the cochlear duct develops two divisions, the scala tympani and scala vestibuli (Fig. 17-10H and I). The internal ear reaches its adult size and shape by the middle of the fetal period (20-22 weeks).

Development of Middle Ears

Development of the tubotympanic recess (Fig. 17-11B) from the first pharyngeal pouch is described in Chapter 10. The proximal part of the tubotympanic recess forms the pharyngotympanic tube (auditory tube). The distal part of the tubotympanic recess expands and becomes the tympanic cavity (Fig. 17-11C), which gradually envelops the auditory ossicles (malleus, incus, and stapes), their tendons and ligaments, and the chorda tympani nerve. All these structures receive a virtually complete epithelial investment. An epithelial-type organizer, located at the tip of the tubotympanic recess, probably plays a role in the early development of the middle ear cavity by inducing programmed cell death—apoptosis. The malleus and the incus develop from the cartilage of the first pharyngeal arch, whereas the stapes develops from the cartilage of the second arch. The tensor tympani, the muscle attached to the malleus, is derived from the mesenchyme in the first pharyngeal arch, and the stapedius muscle is derived from the second pharyngeal arch. During the late fetal period, expansion of the tympanic cavity gives rise to the mastoid antrum, located in the temporal bone. The mastoid antrum is almost adult size at birth; however, no mastoid cells are present in newborn infants. By 2 years, the mastoid cells are well developed and produce conic projections of the temporal bones, the mastoid processes. The middle ear continues to grow through puberty.

Figure 17–11 Development of the external and middle parts of the ear. A, At 4 weeks, showing the relation of the otic vesicle to the pharyngeal apparatus. B, At 5 weeks, showing the tubotympanic recess and pharyngeal arch cartilages. C, At a later stage, showing the tubotympanic recess (primordium of the tympanic cavity and mastoid antrum) beginning to envelop the ossicles. D, Final stage of ear development, showing the relation of the middle ear to the perilymphatic space and the external acoustic meatus.

Development of External Ears

The external acoustic meatus develops from the dorsal part of the first pharyngeal groove. The ectodermal cells at the bottom of this tube proliferate to form a solid epithelial plate, the meatal plug (Fig. 17-11C). Late in the fetal period, the central cells of this plug degenerate, forming a cavity that becomes the internal part of the external acoustic meatus (Fig. 17-11D). The primordium of the tympanic membrane is the first pharyngeal membrane, which separates the first pharyngeal groove from the first pharyngeal pouch (Fig. 17-11A). The external covering of the tympanic membrane is derived from the surface ectoderm, whereas its internal lining is derived from the endoderm of the tubotympanic recess.

The auricle develops from the mesenchymal proliferations in the first and second pharyngeal arches. Prominences—auricular hillocks—surround the first pharyngeal groove (Fig. 17-12A). As the auricle grows, the contribution of the first arch is reduced (Fig. 17-12B to D). The lobule (earlobe) is the last part to develop. The auricle is initially located at the base of the neck (Fig. 17-12A and B). As the mandible develops, the auricle assumes its normal position at the side of the head (Fig. 17-12C and D).

Figure 17–12 Development of the auricle of the external ear. A, At 6 weeks. Note that three auricular hillocks are located on the first pharyngeal arch and three are on the second arch. B, At 8 weeks. C, At 10 weeks. D, At 32 weeks.

Congenital Deafness

Approximately 1 in 1000 newborn infants have significant hearing loss. Congenital deafness may be the result of maldevelopment of the sound-conducting apparatus of the middle and external ears, or of the neurosensory structures in the internal ear. Enlargement of the vestibular aqueduct and endolymphatic duct is the most common congenital ear defect in children with hearing loss (Fig. 17-13). This defect is typically bilateral and is an autosomal recessive condition. Rubella infection during the critical period of development of the internal ear can cause maldevelopment of the spiral organ and deafness. Congenital fixation of the stapes results in conductive deafness in an otherwise normal ear. Failure of differentiation of the anular ligament, which attaches the base of the stapes to the oval window, results in fixation of the stapes to the bony labyrinth and loss of sound conduction.

Figure 17–13 MRI of a 5-year-old child demonstrating bilateral enlargement of vestibular aqueduct and endolymphatic duct (dashed arrow). Also note the cochlea (solid arrow), the medulla (M), and the cerebellum (C).

(Courtesy of Dr. G. Smyser, Altru Health System, Grand Forks, North Dakota.)

Auricular Appendages

Auricular appendages (skin tags) are common and result from the development of accessory auricular hillocks (Fig. 17-14). The appendages usually appear anterior to the auricle, more often unilaterally than bilaterally. The appendages, often with narrow pedicles, consist of skin but they may also contain some cartilage.

Figure 17–14 Child with a rudimentary auricle (microtia) and a preauricular tag. The external acoustic meatus is also absent.

(Courtesy of A.E. Chudley, M.D., Section of Genetics and Metabolism, Department of Pediatrics and Child Health, Children’s Hospital, University of Manitoba, Winnipeg, Manitoba, Canada.)

Clinically Oriented Questions

The answers to these questions are at the back of the book.