Sense Organs

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Chapter 13

Sense Organs

The major sense organs arise in large measure from the thickened ectodermal placodes that appear lateral to the neural plate in the early embryo (see Fig. 6.6). The following descriptions begin with the most cranial placodes and continue to the most caudal. The midline hypophyseal placode, located in the anterior neural ridge (see Fig. 6.6B), becomes the primordium of Rathke’s pouch (the precursor of the adenohypophysis). This structure arises adjacent to the neural tissue that ultimately forms the neurohypophysis. Arising also from the anterior neural region, bilateral olfactory placodes (see Fig. 6.6) are the precursors of the olfactory epithelium. They give rise to olfactory neurons and their supporting cells and to glial cells and neuroendocrine cells that migrate from the placode into the brain. Closely associated with the olfactory placodes is the preneural tissue that forms the functionally associated olfactory bulbs of the brain. The bilateral lens placodes, associated with the optic vesicles (future retina) extending outward from the diencephalic part of the brain, are the lens precursors.

Next in line are the paired trigeminal placodes (cranial nerve V), each of which arises from two placodal precursors—ophthalmic and maxillomandibular (see Fig. 6.6C). The otic placodes (precursors of the inner ear) in the human are the remaining representatives of the dorsolateral series of placodes, all of which produce vibration-detecting organs. In fishes and some amphibians, the other members of the dorsolateral series give rise to the lateral line organs, which serve as vibration and electroreceptors in aquatic vertebrates.

The caudalmost group constitutes the epibranchial placodes, which are located just dorsal to the region where the first through third pharyngeal pouches abut the cervical ectoderm (see Fig. 6.6A). Their specification depends on signals (fibroblast growth factor [FGF] and bone morphogenetic protein [BMP]) emanating from the pharyngeal pouch endoderm. These placodes produce sensory neurons that supply visceral structures. The first epibranchial placode produces neurons (geniculate ganglion of cranial nerve VII) (Fig. 13.1B) that innervate taste buds. Similarly, neurons arising from the second epibranchial placode (inferior [petrosal] ganglion of cranial nerve IX) innervate taste buds, as well as the heart and other visceral organs. The third epibranchial placode contributes to the inferior (nodose) ganglion of the vagus nerve (cranial nerve X), and its neurons innervate the heart, stomach, and other viscera. Of cranial nerves V, VII, IX, and X, the proximal sensory ganglia are derived largely from neural crest cells, and the distal ganglia are principally placodal in origin (see Fig. 13.1B). The placode-derived neurons (those in the distal ganglia) begin to establish peripheral and central connections before axons emerge in the neural crest–derived neuronal precursors in the proximal ganglia.

A major function of both the epibranchial and trigeminal placodes is to produce neurons. The conversion of epithelial cells to neuroblasts in the placodes is accomplished in much the same manner as that which occurs within the neural tube (see Fig. 11.4). Through the process called interkinetic nuclear migration, actual cell division occurs at the apical (in this case, outer) end of the tall epithelial placodal cells. Then the nuclei migrate toward the basal (inner) surface of the cells as they become committed to a neuronal fate as sensory neuroblasts. They then pass through breaches in the basal lamina and migrate internally. There they join other neuroblasts from the same origin to form precursors of the appropriate sensory ganglia.

All the placodes arise from a single preplacodal region, which encircles the cranial neural plate. The preplacodal region is induced by cranial mesoderm, with the neural tube playing a supporting role. The inductive process involves activating the FGF pathway, along with inhibiting Wnt and BMP by their natural antagonists. Levels of BMP must be lower to induce placodes rather than neural crest, and there is a gradient of BMP from highest in the neural plate, to medium for neural crest, and lowest for placodal induction. Characteristic of the induced preplacodal tissue is the expression of the transcription factors, Six and Eya, which promote a generic placodal fate to the cells within the preplacodal region. This is followed by specific secondary inductive signals from different sources that specify the formation of individual placodes (Table 13.1).

Table 13.1

Origins and Inducing Tissues for Cranial Placodes

Placode Origin Inducing Tissue Inducers
Adenohypophysis Anterior neural ridge Anterior neural ridge Shh
Non-neural ectoderm Mesoderm Nodal
Lens Anterior neural ridge Neural plate FGFR
Non-neural ectoderm Mesoderm BMP
Olfactory Anterior neural ridge Anterior neural ridge FGF
Non-neural ectoderm Neural crest  
Otic Neural folds Hindbrain FGF
Non-neural ectoderm Mesoderm FGFR
    Retinoic acid
Trigeminal Non-neural ectoderm Dorsal neural tube PDGF
    Wnt
Epibranchial Non-neural ectoderm Hindbrain FGF
  Mesoderm FGFR

image

BMP, bone morphogenetic protein; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; PDGF, platelet-derived growth factor; Shh, sonic hedgehog.

Modified from McCabe KL, Bronner-Fraser M: Dev Biol 332:192, 2009.

This chapter concentrates on the development of the eyes and ears, the most complex and important sense organs in humans. The organs of smell and taste are discussed in Chapter 14 because their development is intimately associated with the development of the face and pharynx. The sensory components of the cranial nerves are discussed in Chapter 11.

Eye

The eye is a very complex structure that originates from constituents derived from several sources, including the wall of the diencephalon, the overlying surface ectoderm, and migrating cranial neural crest mesenchyme. Two basic themes characterize early ocular development. One is an ongoing series of inductive signals that result in the initial establishment of the major components of the eye. The other is the coordinated differentiation of many of these components.

For normal vision to occur, many complex structures within the eye must properly relate to neighboring structures. The cornea and lens must both become transparent and properly aligned to provide an appropriate pathway for light to reach the retina. The retina must be configured to receive concrete visual images and to transmit patterned visual signals to the proper parts of the brain through neural processes extending from the retina into the optic nerve.

Early Events in the Establishment of the Eye

A single continuous eye field begins to take shape around the area of the prechordal plate during late gastrulation. Cells in the eye field express RAX (retina and anterior neural fold homeobox). Mutations in RAX are the basis for anophthalmia, a rare condition characterized by the absence of any ocular structures in humans. Other prominent markers are Pax-6 and Lhx-2, which are heavily involved in patterning the eye fields (Fig. 13.2). With the secretion of sonic hedgehog (shh) by the prechordal plate and the ventral midline of the diencephalon, Pax-6 expression in the midline is repressed, and the single eye field splits into two separate eye fields, located on either side of the diencephalon. Rax and another important transcription factor, Six-3, protect the ability of the forebrain to secrete shh by suppressing Wnt activity. If Wnt is not suppressed, the anterior region of the developing brain becomes posteriorized and is unable to secrete shh. The absence of Six-3 activity results in the loss of shh secretion and prevents the splitting of the eye fields and leads to the condition of holoprosencephaly and the formation of only one eye (see p. 309 and Fig. 8.18).

Development of the eye is first evident at about 22 days’ gestation, when the lateral walls of the diencephalon begin to bulge out as optic grooves (Fig. 13.3). Within a few days, the optic grooves enlarge to form optic vesicles, which terminate very close to the overlying lens placode in the surface ectoderm. As the optic vesicle expands, the pattern for the future neural retina and retinal pigment epithelium is laid down. Initially, the transcription factor Mitf is expressed throughout the optic vesicle, but the subsequent expression of Vsx-2 in the distal optic vesicle (future neural retina) confines Mitf to more proximal regions, which will become the retinal pigment epithelium. Apposition of the outer wall of the optic vesicle to the surface ectoderm is essential for the transmission of an important inductive message that stimulates the cells of the lens placode to thicken and begin forming the lens (see Fig. 13.2; Fig. 13.4).

The interaction between the optic vesicle and the overlying ectoderm was one of the first recognized inductive processes. It was initially characterized by deletion and transplantation experiments conducted on amphibian embryos. When the optic vesicles were removed early, the surface ectoderm differentiated into ordinary ectodermal cells instead of lens fibers. Conversely, when optic vesicles were combined with certain types of ectoderm other than eye, the ectoderm was stimulated to form lens fibers. Subsequent research on amphibian embryos has shown that series of preparatory inductions from neural plate and underlying mesoderm condition the ectoderm for its final induction into lens by the optic vesicle. In mammals, an important mechanism underlying the severe microphthalmia (tiny eyes) or anophthalmia (absence of eyes) seen in the small eye and fidget mutants is a disturbance in the apposition of optic vesicles and surface ectoderm that interferes with lens induction.

The paired box gene Pax6 plays a prominent role throughout early eye development and at certain later stages of development of the retina and lens. Pax-6 is initially expressed in the lens and the nasal placodes and much of the diencephalon. In Drosophila, Pax6 has been called a master gene for eye development; that is, it can turn on the cascade of genes that guide development of the eye. The power of Pax-6 is shown by the formation of ectopic eyes on antennae and legs in Drosophila when the gene is improperly expressed. In the absence of Pax-6 expression (eyeless mutant), eyes do not form. In the small eye mutation, the mammalian equivalent of eyeless, the early optic vesicle forms, but, as previously noted, eye development does not progress because the surface ectoderm is unable to respond to the inductive signal emitted by the optic vesicle.

The identification in humans of two genes (Eya [eyes absent] and Six [sine oculis]) that are activated by Pax-6 in Drosophila strongly suggests that despite major differences in the structure and development of the vertebrate and insect eye, the basic genetic apparatus has been conserved throughout phylogeny. In mice, Eya-1 and Eya-2 are expressed in the lens placodes and are required for placodal induction and early differentiation, but in the absence of Pax-6 function, they are not expressed, and eye development fails to proceed.

As the process of lens induction occurs, the surface ectoderm stimulates the outer face of the optic vesicle to flatten and ultimately to become concave. This results in the transformation of the optic vesicle to the optic cup (see Fig. 13.3F). The progression from optic vesicle to optic cup requires the expression of Lhx-2 and the action of retinoic acid. In their absence, eye development is arrested at the optic vesicle stage (see Fig. 13.2). Meanwhile, the induced lens ectoderm thickens and invaginates to form a lens vesicle, which detaches from the surface epithelium from which it originated (Fig. 13.5; see Fig. 13.3). Then the lens vesicle takes over and becomes the primary agent of a new inductive reaction by acting on the overlying surface ectoderm and causing it to begin corneal development (see Fig. 13.4).

Formation of the optic cup is an asymmetric process that occurs at the ventral margin of the optic vesicle, rather than at its center. This results in the formation of a gap called the choroid fissure, which is continuous with a groove in the optic stalk (Fig. 13.6). During much of early ocular development, the choroid fissure and optic groove form a channel through which the hyaloid artery passes into the posterior chamber of the eye. Differential expression of Pax genes determines which cells become optic cup (future retina), and which cells become optic stalk (future optic nerve). Through exposure to high concentrations of shh, the expression of Pax-6 is inhibited, and Pax-2 is induced in the optic stalk, whereas a lower concentration of shh more distally permits the expression of Pax-6 in the optic vesicle, thus paving the way toward formation of the retina.

The optic stalk initially represents a narrow neck that connects the optic cup to the diencephalon, but as development progresses, it is invaded by neuronal processes emanating from the ganglion cells of the retina. Pax-2–expressing cells in the optic stalk provide guidance cues to outgrowing retinal axons that pass through the optic nerve and optic chiasm and enter the contralateral optic tract. After the neuronal processes have made their way to the appropriate regions of the brain, the optic stalk is properly known as the optic nerve.

Later in development, the choroid fissure closes, and no trace of it is seen in the normal iris. Nonclosure of the choroid fissure results in the anomaly of coloboma (see Fig. 13.19B). In certain forms of coloboma, especially forms that are associated with anomalies of the kidneys, mutations of Pax-2 genes are seen. In Pax-2–mutant mice, retinal axons do not cross the midline through the optic chiasm, but rather remain in the ipsilateral optic tract.

Formation of the Lens

The lens is derived from cells in the generic preplacodal region, as discussed earlier. From the earliest stages, formation of the lens depends on genetic instructions provided by Pax-6. Pax-6 expression is required for the surface ectoderm to respond to inductive signals (FGF and BMP) from the underlying optic vesicle by activating and combining with another transcription factor, Sox-2. This leads to the thickening of the surface ectoderm to form the lens placode (see Fig. 13.3D). At the same time, migrating neural crest cells, which do not penetrate the space between optic vesicle and prospective lens, give off signals that inhibit cells in other areas of the preplacodal region from forming lens. Inhibition of lens-forming capacity is signaled by the downregulation of Pax-6 by these cells. Pax-6 expression continues as the lens placode invaginates to form the lens vesicle, which ultimately breaks off from the surface ectoderm. At this point, Pax-6 plays a new role in regulating the activity of the genes governing the formation of the lens crystallin proteins.

When it is breaking off from the surface ectoderm, the lens vesicle is roughly spherical and has a large central cavity (see Fig. 13.3E). At the end of the sixth week, the cells at the inner pole of the lens vesicle begin to elongate in an early step toward their transformation into the long, transparent cells called lens fibers (Fig. 13.7A). The influence of the transcriptional regulator Foxe-3, which operates downstream of Pax-6, facilitates the breaking off of the lens vesicle from the surface ectoderm and the transformation of posterior cells into lens fibers.

Differentiation of the lens is a very precise and well-orchestrated process involving several levels of organization. At the cellular level, relatively nonspecialized lens epithelial cells, under the influence of Sox-2, Pax-6, and other proteins paired with an oncogene called Maf, undergo a profound transformation into transparent, elongated cells that contain large quantities of specialized crystallin proteins. At the tissue level, the entire lens is responsive to signals from the retina and other structures of the eye so that its shape and overall organization are best adapted for the transmission of undistorted light rays from the corneal entrance to the light-receiving cells of the retina.

At the cellular level, cytodifferentiation of the lens consists of the transformation of mitotically active lens epithelial cells into elongated postmitotic lens fiber cells. Up to 90% of the soluble protein in these postmitotic cells consists of crystallin proteins. The mammalian lens contains three major crystallin proteins: α, β, and γ.

The formation of crystallin-containing lens fibers begins with the elongation of epithelial cells from the inner pole of the lens vesicle (see Fig. 13.3). These cells become the fibers of the lens nucleus (Fig. 13.8). The remaining lens fibers arise from the transformation of the cuboidal cells of the anterior lens epithelium. During embryonic life, mitotic activity is spread throughout the outer lens epithelial cells. Around the time of birth, mitotic activity ceases in the central region of this epithelium, thus leaving a germinative ring of mitotically active cells surrounding the central region. Daughter cells from the germinative region move into the equatorial region of cellular elongation, where they cease to divide and take on the cytological characteristics of RNA-producing cells and begin to form crystallin mRNAs. These cells soon elongate tremendously, fill up with crystallins, and transform into secondary lens fibers that form concentric layers around the primary fibers of the lens nucleus. The midline region where secondary lens fibers from opposite points on the equator join is recognized as the anterior and posterior lens suture (see Fig. 13.7D). With this arrangement, the lens fibers toward the periphery are successively younger. As long as the lens grows, new secondary fibers move in from the equator onto the outer cortex of the lens.

The crystallin proteins show a very characteristic pattern and sequence of appearance, with the α-crystallins appearing first in the morphologically undifferentiated epithelial cells. Synthesis of β-crystallins is seen when the lens fibers begin to elongate, whereas the expression of γ-crystallins is restricted to terminally differentiated lens fiber cells. Each of the crystallin protein families contains several members. They show different patterns of activation (some members of a family being coordinately activated) and different patterns of accumulation. These patterns facilitate the optical clearing of the lens to allow the efficient transmission of light.

Throughout much of its life, the lens is under the influence of the retina. After induction of the lens, secretions of the retina, of which FGF is a major component, accumulate in the vitreous humor behind the lens and stimulate the formation of lens fibers. A striking example of the continued influence of the retina on lens morphology is seen after a developing lens is rotated so that its outer pole faces the retina. Very rapidly, under the influence of retinal secretions, the low epithelial cells of the former outer pole begin to elongate and form an additional set of lens fibers (Fig. 13.9). A new lens epithelium forms on the corneal side of the rotated lens. Such structural adaptations are striking evidence of a mechanism that ensures correct alignment between the lens and the rest of the visual system throughout development.

Formation of the Cornea

Formation of the cornea is the result of the last of the series of major inductive events in eye formation (see Fig. 13.4), with the lens vesicle acting on the overlying surface ectoderm. This induction results in the transformation of a typical surface ectoderm, consisting of a basal layer of cuboidal cells and a superficial periderm, to a transparent, multilayered structure with a complex extracellular matrix and cellular contributions from several sources. In keeping with its multifaceted role at almost all stages of eye development, Pax-6 expression in the surface ectoderm is a requirement for corneal induction.

The inductive influence of the lens stimulates a change in the basal ectodermal cells. These cells increase in height, largely as a result of the elaboration of secretory organelles (e.g., Golgi apparatus) on the basal ends of the cells. As these changes are completed, the cells begin to secrete epithelially derived collagen types I, II, and IX to form the primary stroma of the cornea (Fig. 13.10).

Using the primary stroma as a basis for migration, neural crest cells around the lip of the optic cup migrate centrally between the primary stroma and the lens capsule. Although mesenchymal in morphology during their migration, these cells become transformed into a cuboidal epithelium called the corneal endothelium when their migration is completed. At this point, the early cornea consists of (1) an outer epithelium, (2) a still acellular primary stroma, and (3) an inner endothelium.

The migration of neural crest cells between the lens and overlying ectoderm is subject to tight developmental control. A positive stimulus for migration is the production of transforming growth factor-β (TGF-β) by the lens. Modulating this influence is the presence of semaphorin 3A on the lens. The periocular neural crest cells express neuropilin-1, which, when combined with semaphorin, inhibits migration. At a critical time in development, a subpopulation of these neural crest cells ceases to express neuropilin. These cells are then able to migrate between the lens and corneal epithelium. A similar mechanism allows the penetration of sensory nerve fibers into the cornea.

After the corneal endothelium has formed a continuous layer, its cells synthesize large amounts of hyaluronic acid and secrete it into the primary stroma. Because of its pronounced water-binding capacities, hyaluronic acid causes the primary stroma to swell greatly. This provides a proper substrate for the second wave of cellular migration into the developing cornea (Fig. 13.11). These cells, also of neural crest origin, are fibroblastic. They migrate and proliferate in the hyaluronate-rich spaces between layers of collagen in the primary corneal stroma. The migratory phase of cellular seeding of the primary corneal stroma ceases when these cells begin to produce large amounts of hyaluronidase, which breaks down much of the hyaluronic acid in the primary stroma. In other parts of the embryo (e.g., limb bud), there is also a close correlation between high amounts of hyaluronic acid and cellular migration and a cessation of migration with its removal. With the removal of hyaluronic acid, the cornea decreases in thickness. When the migratory fibroblasts have settled, the primary corneal stroma is considered to have been transformed into the secondary stroma.

The fibroblasts of the secondary stroma contribute to its organization by secreting coarse collagen fibers to the stromal matrix. Nevertheless, prominent layers of acellular matrix continue to be secreted by epithelial and endothelial cells of the cornea. These secretions provide the remaining layers that constitute the mature cornea. Listed from outside in, they are (1) the outer epithelium, (2) Bowman’s membrane, (3) the secondary stroma, (4) Descemet’s membrane, and (5) the corneal endothelium (see Fig. 13.10

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