Regulation of p27 kip1 by Sox2 maintains quiescence of inner pillar cells in the murine auditory sensory epithelium

Abstract

Sox2 plays critical roles in cell fate specification during development and in stem cell formation; however, its role in postmitotic cells is largely unknown. Sox2 is highly expressed in supporting cells (SCs) of the postnatal mammalian auditory sensory epithelium, which unlike non-mammalian vertebrates remains quiescent even after sensory hair cell damage. Here, we induced the ablation of Sox2, specifically in SCs at three different postnatal ages (neonatal, juvenile and adult) in mice. In neonatal mice, Sox2-null inner pillar cells (IPCs, a subtype of SCs) proliferated and generated daughter cells, while other SC subtypes remained quiescent. Furthermore, p27 Kip1, a cell cycle inhibitor, was absent in Sox2-null IPCs. Similarly, upon direct deletion of p27 Kip1, p27 Kip1-null IPCs also proliferated but retained Sox2 expression. Interestingly, cell cycle controlofIPCs bySox2-mediated expressionofp27 Kip1 gradually declined with age. In addition, deletion of Sox2 or p27 Kip1 did not cause a cell fate change. Finally, chromatin immuno precipitation with Sox2 antibodies and luciferase reporter assays with thep27 Kip1 promoter support that Sox2 directly activatesp27 Kip1 transcription in post mitotic IPCs. Hence, in contrast to the well known activityofSox2inpromotingproliferationand cell fate determination, our data demonstrate that Sox2 plays a novel role as a key upstream regulator of p27 Kip1 to maintain the quiescent state of postmitotic IPCs. Our studies suggest that manipulating Sox2 or p27 Kip1 expression is an effective approach to inducing proliferation of neonatal auditory IPCs, an initial but necessary step toward restoring hearing in mammals. © 2012 the authors.