We propose a model in which HBCs are released from this inhibition upon downregulation of p63, which allows these stem cells to differentiate into fully mature olfactory neurons and other cell types according to a prescribed differentiation program. Our discovery of p63 as a key regulator of HBC dynamics provides important insight into the cellular mechanisms regulating this multipotent neural progenitor and implicates a larger p63-dependent transcriptional network that drives cell fate decisions between self-renewal and differentiation in the postnatal olfactory

stem cell. Through what cellular mechanisms does p63 promote self-renewal of the olfactory stem cell? Unlike other epithelial stem cells, which are proliferative, HBCs are largely quiescent under normal conditions. Because p63 is expressed in both quiescent and proliferating learn more HBCs, if p63 is indeed required for self-renewing proliferation, it must work in concert with other factors in the cell to govern the transition from quiescence to proliferation. In other epithelial systems, p63 appears to support stem cell self-renewal in vivo by antagonizing apoptosis or senescence (Senoo et al., 2007 and Su et al.,

2009b). Similarly, in the central nervous system, MI-773 nmr p63 antagonizes p53 activity to promote

the survival of embryonic cortical neural precursor cells and newly born cortical neurons (Dugani et al., 2009). Although it is formally possible that p63 inhibits apoptosis of newly born HBCs in order to promote stem cell survival following HBC cell division, we did not in fact however observe a statistically significant increase in caspase 3-positive cells in the p63 mutant background. Future studies should help illuminate the contributions of p63 function to the processes of olfactory stem cell proliferation and stem cell survival. In the first studies demonstrating p63′s function in development, germline deletion of the p63 gene resulted in severe defects in the development of the skin and other stratified epithelia ( Mills et al., 1999 and Yang et al., 1999). One group observed a depletion of the proliferative stem cells but persistence of a small number of differentiated cells, which was interpreted to reflect a requirement for p63 in stem cell self-renewal, but not for differentiation ( Yang et al., 1999). The defects in epidermal stratification and the paucity of differentiated cells were ascribed to a depletion of the proliferative stem cells in the developing epithelium owing to the lack of self-renewal ( Yang et al., 1999).