Hair Cell Development in Higher Vertebrates

Abstract

Mammalian inner ear morphogenesis and production of hair cells are influenced by local cellular interactions and regulated by specific genes. In particular, Notch–Notch ligand interaction–mediated lateral inhibition plays an important role in the determination of hair cell fate. Inactivation or disruption of Notch signaling can lead to the production of supernumerary hair cells. Specific basic helix-loop-helix (bHLH) transcript factors have been shown to act downstream of Notch signaling and are essential for initial hair cell differentiation. Whereas Math1, a mouse homologue of the Drosophila gene atonal, is a positive regulator of hair cell differentiation, Hes1 and Hes5, mammalian hairy and enhancer of split homologues, act as negative regulators. These bHLH transcription factors are expressed in the inner ear epithelial region at the time when hair cell differentiation occurs. Whereas targeted deletion of Math1 gene leads to failure of hair cell differentiation, misexpression of Math1 induces production of extra hair cells, and cotransfection of Hes1 and Math1 in postnatal rat cochlear explant cultures results in an inhibition on hair cell differentiation induced by Math1. In addition, specific growth factors and cell cycle regulators that influence proliferation of sensory epithelial progenitors may also affect hair cell differentiation. Furthermore, other transcription factors, including Brn3c, Barhl1, and Gfi1, are required for further maturation and maintenance of hair cells. Understanding of hair cell differentiation mechanisms may provide useful hints for stimulating hair cell regeneration in mature inner ears, which could eventually be helpful for both recovery of hearing and recovery from balance impairment induced by hair cell loss.