Development of the ear

Inner ear

The production of a precisely positioned and functionally well-tuned inner ear depends on genetic patterning and a cascade of transcription signals expressed by numerous tissues, including the developing inner ear and its surrounding periotic mesenchyme, the adjacent hindbrain, neural crest and notochord ( , ).

The first signs of inner ear development are visible shortly after those associated with the developing eyes. Two patches of ectodermal thickening, the otic placodes, appear lateral to the hindbrain at stage 9. Each placode invaginates as an otic pit, adjacent to rhombomeres 5 and 6 of the hindbrain and dorsal to the second pharyngeal cleft ( Ch. 17 ; see Fig. 17.1B ). During stage 12 (30–32 days postfertilization, see Fig. 23.3 ) the pit is pinched off from the surface ectoderm to form a simple, hollow epithelial sac, the otic vesicle (otocyst or auditory vesicle) ( Fig. 16.1 ).

Regions of the vesicle differentiate into prosensory domains, which give rise to the membranous labyrinth and the vestibulocochlear (statoacoustic) ganglia of the eighth cranial nerve. The first morphological evidence of this differentiation is visible during stage 14 (postfertilization days 32–34), when the otic vesicle loses its initial piriform shape. A tubular diverticulum, the endolymphatic appendage, develops from its dorsomedial rim. The remainder of the vesicle, the utriculosaccular chamber, differentiates into an expanded pars superior and a narrower pars inferior. The endolymphatic appendage elongates and its tip expands into an endolymphatic sac that is connected to the pars superior by a narrow endolymphatic duct.

Two plate-like diverticula, one vertical and one horizontal, emerge from the dorsal part of the pars superior. The epithelia in the centre of each outgrowth coalesce to form a fusion plate; the central part of this plate is eventually resorbed, leaving the anlagen of the semicircular canals. The vertical plate gives rise to the anterior and posterior semicircular canals, which share a common crural attachment to the utriculosaccular chamber, and the horizontal plate gives rise to the lateral semicircular canal. A small expansion, the ampulla, forms at one end of each semicircular canal.

The central part of the utriculosaccular chamber, which now represents the membranous vestibule, becomes divided into a small ventral saccule and a larger dorsal utricle, mainly by horizontal infolding extending from the lateral wall of the chamber towards the opening of the endolymphatic duct. In this way, communication between the utricle and saccule is restricted to a narrow utriculosaccular duct. The latter becomes acutely bent on itself; its apex is continuous with the endolymphatic duct. While this is happening, the membranous labyrinth rotates so that its long axis, which was originally vertical, becomes more or less horizontal.

The ventral tip of the pars inferior begins to elongate. A medially directed evagination, the cochlear anlagen, is evident in the ventral part of the utriculosaccular chamber by stage 15. The proximal region of this cochlear duct continues to increase in length and its distal region becomes progressively more coiled, reaching 2.5 turns by postfertilization week 10 ( Fig. 16.2 ) ( ). When the duct has achieved its final length and spiral configuration, its proximal part becomes constricted, forming the ductus reuniens by which the saccule remains connected to the cochlea. The cochlea is initially patterned into several prosensory domains. The central domain will give rise to the organ of Corti. Molecular signals regulating the induction and differentiation of the organ of Corti are complex ( , ): a combination of bone morphogenetic protein (BMP), fibroblast growth factor and Notch signalling is required to define the sensory and non-sensory territories in the cochlear duct ( , ).

Cells derived from the otocyst differentiate into the bipolar neurones that populate the vestibular and cochlear ganglia; sustentacular cells ( ); the unique endolymph-producing epithelia of the stria vascularis; the absorbing epithelia of the endolymphatic sac; the general epithelial lining of the membranous labyrinth; and specialized cells in the six sensory patches of the inner ear (crista ampullaris of the three semicircular canals, maculae of the utricle and saccule, organ of Corti in the cochlea). Each of the sensory patches consists of mechanosensory hair cells and non-sensory supporting cells arranged into mosaic patterns that are essential for normal hearing and balance. The only cells in the mature inner ear that are not of otocyst origin are melanocytes in the stria vascularis, derived from the neural crest.

The very different morphologies of the mature cristae, maculae and organ of Corti reflect the differential expression of multiple genes during their development and maturation. The formation of the utricle and saccule occurs during a time that coincides with the initiation of hair cell planar polarity. The development of core planar cell polarity in the orientation of stereocilia in the mechanosensory hair cells of the mammalian inner ear is described in an extensive and conflicting literature ( , ).

At the same time as these changes are taking place, mesenchymal cells surrounding the developing membranous labyrinth undergo chondrogenesis to form an encasing cartilaginous otic capsule. Between postmenstrual weeks 16–23 the otic capsule ossifies to form almost all of the bony labyrinth of the internal ear within the petrous temporal bone; the modiolus and osseous spiral lamina ossify directly from connective tissue. The cartilaginous capsule is initially incomplete and the cochlear, vestibular and facial ganglia are temporarily exposed in the gap between its canalicular and cochlear parts. They subsequently become covered by an outgrowth of cartilage that will enclose the facial nerve.

Vacuoles filled with perilymph develop in the embryonic connective tissue between the cartilaginous capsule and the epithelial wall of the membranous labyrinth. The rudiment of the periotic cistern or vestibular perilymphatic space can be seen in the reticulum between the saccule and fenestra vestibuli by stage 17. The cochlear scalae (scala vestibuli and scala tympani) develop by fusion of these spaces; the mechanism is uncertain ( ). The two scalae gradually extend along each side of the cochlear duct and a communication, the helicotrema, opens between them when they reach the tip of the coiled duct. An overview of human inner ear development is given in .

The rudiment of the eighth cranial nerve appears in stage 13 as the vestibulocochlear (statoacoustic) ganglion that lies between the otocyst and the hindbrain and is initially temporarily fused with the ganglion of the facial nerve. Neuroblasts (fate already specified in the ectoderm of the otic placode) delaminate from the anteroventral region of the otic vesicle, proliferate and migrate to the site of the presumptive ganglion, where they coalesce. They differentiate into mature bipolar sensory neurones and become segregated into vestibular and spiral ganglia, each associated with the corresponding division of the eighth cranial nerve. These neurones are unusual because they are exclusively placodal in origin, unlike neurones in most cranial ganglia with a dual placodal and neural crest origin, and many of their somata become enveloped in thin myelin sheaths. Their peripheral processes collectively provide the afferent innervation of the labyrinthine hair cells, relaying balance and auditory information. Tantalizing evidence about the transcriptional networks that encode the positioning of sensory hair cells and spiral ganglion neurones along a frequency (tonotopic) gradient within the developing cochlea, and that ensure that the two cell types make appropriate functional connections, is appearing in animal models ( , , ). The olivocochlear bundle, an outgrowth of axons from neurones in the superior olivary complexes in the pons, accompanies the axons of the developing eighth cranial nerve; these axons provide the inner ear with an efferent innervation, mainly to the outer hair cells in the organ of Corti, where they are associated with modulation of hearing. In utero , the fetus receives sound by bone conduction. interaural sound differences are not established until birth, whether preterm or term.