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Molecular Genetics of Vestibular Organ Development

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Molecular Genetics of Vestibular Organ Development HVS2 11/18/2003 3:02 PM Page 11 2 Molecular Genetics of Vestibular Organ Development Weise Chang,Laura Cole,Raquel Cantos, and Doris K. Wu 1. Introduction Normal development of the vertebrate inner ear depends on signals ema- nating from multiple surrounding tissues, including the hindbrain, neural crest, mesenchyme, and notochord (for reviews, see Fritzsch et al. 1998; Torres and Giraldez 1998; Fekete 1999; Kiernan et al. 2002). Primarily through the analyses of mutant mice with spontaneous mutations or tar- geted deletions (knockouts), several genes involved in the patterning of the inner ear have been identified. Analyses of the phenotypes resulting from mutations within some of these genes, as well as analyses of their spatial and temporal expression patterns, indicate that they play specific, and sometimes multiple, roles in the patterning of the vestibular and auditory components of the inner ear (Table 2.1). Here, we summarize our current knowledge of the molecular mechanisms governing the development of the inner ear and the roles played by a variety of genes, focusing on the vestibu- lar apparatuses of the chicken and mouse. 2. Gross Development of the Vestibular Apparatus The membranous portion of the vertebrate inner ear originates from a thickening of the ectoderm adjacent to the hindbrain (Fig. 2.1). This thickened epithelium, known as the otic placode, invaginates to form the otic cup, which closes to form the otic vesicle/otocyst. A subpopulation of epithelial cells in the anteroventral lateral region of the otic cup and otic vesicle delaminate and coalesce to form the eighth (vestibulocochlear) ganglion. The otic vesicle proper undergoes a series of elaborate morpho- genetic changes to give rise to an intricate, mature inner ear. Figure 2.2 illustrates the gross development of the mouse inner ear from a late stage of otic vesicle formation through maturity, a period covering the complete development of the vestibular apparatus (Morsli et al. 1998). The vestibular component of the inner ear develops largely from the dorsal 11 HVS2 11/18/20033:02PMPage12 12 W. Changetal. Table 2.1. Genes affecting vestibular patterning. Type of Distribution in the inner Ear Gene Human disease protein and surrounding structures Mutant or knockout phenotype Ref. Bmp4 — secreted factor three presumptive cristae, Bmp4 +/-: absence of lateral canal Morsli et al. 1998; Hensen’s and Claudius’ Teng et al. 2000 regions of the cochlea Brn4/ DFN3 POU domain periotic mesenchyme Brn4 -/-, Slf: defects in fibroblasts de Kok et al. 1995; Pou3f4 transcription of spiral ligament; shortened Phippard et al. 1998, factor cochlea; constricted superior canal 1999; Minowa et al. 1999 Dlx 5 — homeobox dorsal posterior region of otic no anterior or posterior canal; Acampora et al. 1999b; transcription vesicle; semicircular canals reduced lateral canal; poorly Depew et al. 1999; factor and endolymphatic duct; formed cristae; reduced maculae; Merlo et al. 2002 sensory epithelium abnormal endolymphatic duct and cochlea Eya 1 Branchial- transcription ventrolateral otic vesicle; no eighth ganglion; amorphic inner Abdelhak et al. 1997; oto-renal coactivator eighth ganglion; neurogenic ear Xu et al. 1997, 1999; syndrome and sensory regions Kalatzis et al. 1998; Fgf3 — growth factor r5 and r6; prospective otic no endolymphatic duct or sac; Mansour et al. 1993; placode region; neurogenic reduced spiral ganglion; enlarged Mansour 1994; and sensory regions membranous labyrinth McKay et al. 1996 Fgf10 growth factor neurogenic area; all lacks all three canals and the Pauley et al. 2003 prospective sensory patches; posterior crista; malformed anterior vestibular and spiral ganglia crista Fgfr2 — growth factor otic placode; dorsal and rudimentary inner ear with no Pirvola et al. 2000 (IIIb) receptor medial wall of otic vesicle; sensory organs; loss of eighth nonsensory regions of the ganglion; 50% of mutants lack inner ear endolymphatic duct HVS2 11/18/20033:02PMPage13 Fidgetin — AAA protein epithelial cells in canal fidget: missing lateral canal; Cox et al. 2000 outpocket; cochlear duct malformed anterior and posterior canals GATA3 HDR syndrome zinc-finger regions of periotic rudimentary inner ear with a poorly Karis et al. 2001 transcription mesenchmye around developed endolymphatic duct; factor prospective canal region; misrouted efferent projections hindbrain; vestibular sensory 2. OrganDevelopmentVestibular MolecularGeneticsof 13 components except the saccule; cochlear duct Gli3 — zinc-finger periotic mesenchyme Extratoes: truncated anterior canal; Schimmang et al. 1992; transcription no lateral canal, but lateral crista is Hui et al. 1994 factor present Hmx2 — homeobox anterodorsal region of otic absence of three canals and cristae, Wang et al. 2001 (Nkx5.2) transcription vesicle; canals and ampullae; fusion of the utricle and saccule factor utricle, saccule, and endolymphatic duct; stria vascularis of the cochlea Hmx3 — homeobox otic placode; canal outpocket; reduced anterior canal, missing Hadrys et al. 1998; (Nkx5.1) — transcription semicircular canals posterior and lateral canals, loss of Wang et al. 1998 factor lateral crista (Bober’s group); missing lateral crista and ampulla, fusion of utricle and saccule (Lufkin’s group) Hoxa1 — homeobox 8 dpc: r3/4 boundary to spinal no endolymphatic duct or sac; Gavalas et al. 1998 transcription cord amorphic inner ear; no organ of factor Corti; reduced eighth ganglion Hoxa1/ — homeobox Hoxb1: 8 dpc: r3/4 boundary amorphic inner ear—more severe Rijli et al. 1993; Hoxb1 transcription to spinal cord; 9 dpc: than Hoxa1 alone Maconochie et al. 1996 factors expression up-regulated in r4 HVS2 11/18/20033:02PMPage14 14 W. Changetal. Table 2.1. Continued Type of Distribution in the inner Ear Gene Human disease protein and surrounding structures Mutant or knockout phenotype Ref. Hoxa2 — homeobox r1/2 boundary to spinal cord; enlarged membranous labyrinth; Deol 1964; Cordes and transcription expression up-regulated in r3 scala vestibuli lacking or collapsed Barsh 1994; McKay et factor and r5 al. 1996 Jagged1/ Allagille syndrome Transmembrane all prospective sensory Htu, Slm: small or missing one or Adam et al. 1998; Serrate 1 protein, Notch organs; later restricts to both anterior and posterior Kiernan et al. 2001; ligand supporting cells; ampullae and canals; decreased Tsai et al. 2001 subpopulation of outer hair cell number and endolymphatic duct cells increased inner hair cell number Kreisler — bZIP r5 and r6 misplaced otocyst; inner ear usually Deol 1964; Cordes and transcription cyst-like Barsh 1994; McKay et factor al. 1996; Ma et al. 1998, 2000 Lmx1a — LIM dorsal and lateral regions of Dreher: distended endolymphatic Giraldez 1998; homeodomain otic vesicle duct and sac; constricted canals; Millonig et al. 2000 protein poorly coiled cochlea Netrin 1 — secreted central region of canal defect in fusion plate formation; Salminen et al. 2000 protein, related outpocket; semicircular reduced anterior canal; no posterior to laminin canals; nonsensory region of or lateral canal utricle, saccule, and cochlea NeuroD — HLH neurogenic area and eighth severe reduction in eighth ganglion; Liu et al. 2000; transcription ganglion; all sensory regions shortened cochlear duct Kim et al. 2001 factor HVS2 11/18/20033:02PMPage15 Ngn1 — bHLH anteroventrolateral otic no eighth ganglion; fusion of utricle Ma et al. 2000 transcription vesicle and saccule; reduced utricle and factor saccule; shortened cochlea Nor-1 — nuclear receptor central region of canal thin semicircular canals and Ponnio et al. 2002 transcription outpocket; semicircular flattened ampullae 2. OrganDevelopmentVestibular MolecularGeneticsof 15 factor canals Otx1 — transcription lateral wall of otic vesicle; no lateral canal or ampulla; no Acampora et al. 1996; factor lateral canal and ampulla; lateral crista; incomplete separation Morsli et al. 1999 lateral wall of saccule and of utricle and saccule; misshapen cochlea saccule and cochlea Otx2 — transcription ventral tip of otic vesicle; Otx1-/-, Otx2+/-: incomplete Morsli et al. 1999; factor lateral wall of saccule and separation of utricle and saccule; Cantos et al. 2000 cochlea misshapen saccule and cochlea Pax3 Waardenberg paired box dorsal half of neural tube Splotch: aberrant endolymphatic Deol 1966; Epstein et syndrome type I transcription duct; misshapen cochlear and al. 1991; Goulding et factor vestibular components al. 1991, 1993 Prx1/Prx2 — paired-related Prx1—periotic mesenchyme Prx1-/-, Prx2-/-: no lateral canal; ten Berge et al. 1998 homeobox Prx2—otic epithelum; reduced anterior and posterior transcription periotic mesenchyme canals; smaller otic capsule factor Shh Holoprosencephaly secreted factor notochord and floor plate of absence of the lateral canal and Liu et al. 2002; neural tube, otic epithelium crista; no discernible ampulla, Riccomagno et al. 2002 and ganglion utricle, saccule, cochlea, and endolymphatic duct; reduced cochleovestibular ganglion HVS2 11/18/2003 3:02 PM Page 16 16 W. Chang et al. Figure 2.1. A schematic diagram summarizing the stages of inner ear development from an otic placode to an otic vesicle. These stages span approximately 8.5–9.5dpc (days postcoitium) in mice, and embryonic days 1.5–2.5 (Hamburger and Hamilton stages 9–17) in chickens. Orientations: D, dorsal; M, medial. (Adapted from Wu and Choo 2003.) Figure 2.2. Lateral views of paint-filled membranous labyrinths of mice from 11.5dpc to postnatal day 1. Specimens were fixed in paraformaldehyde, dehydrated in ethanol, and cleared in
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