, 2009), reflecting the hair cell production during regeneration. The expression of Atoh1 in support cells occurs rapidly after hair cell damage in the BP, near the time when these cells enter the mitotic cell cycle. Studies in zebrafish lateral line have shown that Notch pathway components are also upregulated very soon after hair cell damage in this system (Ma et al., 2008) and that blocking the Notch pathway using a gamma-secretase inhibitor leads to an excess of find more regenerated hair cells. Similar results were obtained in chick BP (Daudet

et al., 2009). These studies indicate that the mechanisms of lateral inhibition function during regeneration much like they would during normal development; however, there are two additional

interesting findings. First, in the chick, Atoh1 is upregulated in support cells of the chick basilar papilla very soon after damage, possibly before the cells enter the cell cycle. Second, the experimental inhibition of Notch in the undamaged basilar papilla or lateral line does not activate Atoh1 expression in the support cells and does not induce transdifferentiation of support cells to hair cells. These results indicate that it is only after damage, when the Notch pathway is upregulated in the BP, that Notch-mediated lateral inhibition is important for defining the fates ON-01910 price of the hair and support cells. Notch does not appear to be necessary for the maintenance of these fates in the undamaged epithelium. Since the loss of hair cells induces the rapid upregulation of Atoh1 in the support cells, it also suggests that a different type of signal produced by the hair cells normally inhibits the expression of the proneural Atoh1 transcription factor in the neighboring support cells. Although cell proliferation and transdifferentiation are virtually absent in the normal mature

inner ear epithelia of mammals, these processes can occur in neonatal mammals. Dissociation of the support cells from the cochlea and vestibular TCL epithelia from neonatal mice allows them to proliferate in vitro and turn on markers of hair cells, Myosin VIIa and Atoh1 (Diensthuber et al., 2009, Martinez-Monedero et al., 2007, Oshima et al., 2009 and White et al., 2006). However, this proliferative ability is limited to the first 2 weeks of postnatal development in the cochlea of mice, though the vestibular organs may harbor these putative stem cells into adulthood. In addition to these examples of proliferation, the decline in potential for transdifferentiation with maturation has also been examined in the cochlea. The Notch pathway remains active for a brief period of postnatal development (Hartman et al., 2009); however, after postnatal day 3 in the mouse, inhibition of this pathway no longer leads to Deiters’ cell transdifferentiation (Hayashi et al., 2008a and Yamamoto et al., 2006).