Specification of the mammalian cochlea is dependent on Sonic hedgehog

Abstract

The mammalian inner ear is a complex sensory organ comprised of auditory and vestibular structures that serve to coordinate the senses of hearing and balance, respectively. The inner ear develops over a protracted period originating from a thickening of surface ectoderm, the otic placode, which forms at the level of the prospective hindbrain upon inductive influences from neighboring tissues (Groves and Bronner-Fraser 2000;Ladher et al. 2000). Once induced, the otic placode invaginates to form the otic cup and shortly thereafter pinches off from the surface ectoderm to give rise to the otic vesicle. Over the next several days the otic vesicle undergoes an intense period of proliferation, differentiation, and morphogenesis culminating in the establishment of the ventrally derived auditory component of the inner ear, the cochlea, as well as the more dorsally derived vestibular apparatus, comprising the semicircular canals, utricle, and saccule (for review, see Torres and Giraldez 1998).Grafting and lineage tracing experiments performed in the chick, in addition to mutational analyses performed in the mouse, have confirmed that the fate of inner ear progenitors is specified early in development (Baker and Bronner-Fraser 2001). By the otic vesicle stage, numerous genes showing restricted patterns of expression compartmentalize the otic epithelium along its three major axes (Fekete and Wu 2002). With respect to the auditory component of the inner ear, the expression of several genes in the ventral and ventromedial regions of the otocyst, including the overlapping expression of the homeobox transcription factors Otx1 and Otx2 as well as the paired-box gene Pax2 mark the location of cochlear duct outgrowth (Fekete and Wu 2002). For vestibular development, the homeobox transcription factors Hmx2, Hmx3, and Dlx5 in the dorsolateral region of the otocyst mark the territory contributing to semicircular canal formation (Fekete and Wu 2002). Loss-of-function studies in the mouse confirm that each of these genes participates actively in establishing regional identity within the inner ear (Acampora et al. 1996(Acampora et al. , 1999Torres et al. 1996;Hadrys et al. 1998;Wang et al. 1998Wang et al. , 2001Depew et al. 1999;Morsli et al. 1999).In addition to the establishment of regional identity, a number of genes have also been identified that have an impact on the specification of distinct cell fates within the otocyst. The inner ear is a self-contained organ in that the majority of cell types contributing to its development including sensory, nonsensory, and neurogenic are derived from the otic epithelium (Torres and Giraldez 1998). For instance, within the anteroventral region of the otic vesicle, cells expressing the bHLH transcription factors Neurogenin-1 (Ngn1) and NeuroD form the neuronal lineage, giving rise to the cochleovestibular

Ablation studies on the developing inner ear reveal a propensity for mirror duplications

“…Whereas Hh signaling in zebrafish plays an important role in anteroposterior patterning, in mouse and chicken, it appears to play a different role. Loss of Hh signaling in mouse, as seen in the Shh knockout, results in loss of ventral molecular markers and structures, such as the cochlea and cochleovestibular (otic) ganglion, whereas ectopic activation of Hh signaling dorsally results in down-regulation of dorsal markers and the turning on of some ventral markers (Riccomagno et al, 2002). Hh signaling is also important for inhibiting the expression of more dorsal genes, such as Wnt, ventrally (Riccomagno et al, 2005;Ohyama et al, 2006).…”

“…This finding contrasts with the role of Hh signaling in mouse inner ear development, where Sonic hedgehog (Shh) plays a role in dorsoventral patterning by promoting ventral identity and restricting Wnt genes to the dorsal region (Riccomagno et al, 2002(Riccomagno et al, , 2005Ohyama et al, 2006). In chickens, Shh has also been shown to be important for ventral patterning of the otocyst (Bok et al, 2005).…”

Retinoic acid down‐regulates Tbx1 expression in vivo and in vitro

“…Neither Shh nor Foxa2 was down-regulated in the pharyngeal endoderm or head mesenchyme, and two further pieces of evidence suggest that it is unlikely that the RA repression of Tbx1 in pharyngeal endoderm is mediated by a decrease in expression of Shh or Foxa2. Firstly, axial expression of Shh exerts a long-range signaling effect upon the otic vesicle, but in Shh null mice, Tbx1 expression in the otic epithelium is maintained (Riccomagno et al, 2002), whereas in RA bead experiments otic Tbx1 is completely lost. Secondly, pharyngeal expression of Tbx1 is abnormal in the VAD quail at all stages, but expression of Shh is normal at stage 11 in the presumptive second pharyngeal pouch (Quinlan et al, 2002).…”

Molecular Genetics of Vestibular Organ Development

“…Identifying possible upstream signaling molecules and downstream targets for this transcriptional factor, whether they are epithelium-or mesenchyme-derived, will be important. It is interesting that, in the Shh mutants, both Brn4 and Tbx1 are down-regulated in the otic mesenchyme (Riccomagno et al 2002). The otic capsule is reduced in Shh mutants, indicating that other molecular pathways that mediate otic chondrogenesis are not perturbed by the loss of Shh.…”

“…The delamination of neuroblasts from the anteroventral region of the otic cup or otocyst is also affected in these mutant ears. Even though it has been postulated that SHH released from the ventral midline patterns the inner ear (Riccomagno et al 2002), the presence of low levels of Shh within the otic epithelium has been reported (Liu et al 2002). Although the source of SHH for patterning the inner ear remains an open question, it is clear that the otic epithelium responds directly to SHH as indicated by the presence of Patched (receptor for Shh) and Gli1 (a downstream target of Shh) mRNA transcripts within the epithelium (Liu et al 2002;Riccomagno et al 2002).…”