During development of the sensory epithelium in the cochlea, the

During development of the sensory epithelium in the cochlea, the Cdki, p27kip1 is an early marker of the part of the presumptive sensory region that will generate the hair cells and support cells ( Chen and Segil, 1999) and deletion of p27kip1 leads to an extension in the normal developmental limit in proliferation of cells in the cochlea ( Kil et al., 2011, Lee et al., 2006 and Löwenheim et al., 1999). Although these experiments demonstrated that p27kip1 is an important developmental regulator of support

cell proliferation, recently it was shown that deletion of p27kip1 in adult animals also causes support cells to enter the mitotic cell cycle ( Oesterle et al., 2011), albeit in small numbers, indicating this website that p27kip1 Bortezomib is one of the factors required in mature

mice to maintain mitotic quiescence in the support cells. Taken together, the results suggest that methods to stimulate proliferation in the mammalian inner ear epithelia might be possible through manipulation of a combination of known pathways. However, even though some support cells proliferate in the postnatal cochlea in the p27kip1 knockout mice, very few, if any, generate mature new hair cells as they would during regeneration in nonmammalian vertebrates; rather, the proliferating cells appear to generate additional support cells, or else they undergo apoptosis. This leads to the second main difference between the nonmammalian vertebrates and mammals: the support cells of the auditory sensory epithelium of nonmammalian vertebrates have the capacity to transdifferentiate into hair cells, while mammalian cochlear support cells do not. What factors enable the support cells of nonmammalian vertebrates to differentiate into hair cells after damage? Studies of the factors that control the fates of hair cells and support cells during regeneration have focused on the developmental regulators of hair cell determination/differentiation: the bHLH transcription

factor, Atoh1, and the Notch pathway (Cafaro et al., 2007, Daudet et al., 2009 and Stone and Rubel, 1999). Atoh1 is a critical transcription much factor for the specification of the hair cells during development (Figure 3), while Notch signaling has both a “prosensory” role and acts in a more conventional lateral inhibitory manner to regulate the ratios of hair and support cells. (Brooker et al., 2006, Kiernan et al., 2001, Kiernan et al., 2006, Adam et al., 1998, Brooker et al., 2006, Haddon et al., 1998, Kiernan et al., 2005 and Zine and de Ribaupierre, 2002). In the normal adult vestibular organs in birds, Atoh1 is expressed in scattered cells throughout the epithelium, suggesting a continued requirement for specification during the ongoing hair cell production in these organs (Cafaro et al., 2007). By contrast, in the normal avian adult BP, there is no Atoh1 expression; however, after hair cell damage a number of cells express Atoh1 and Notch pathway genes (Cafaro et al.

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