Regulation of p27Kip1 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, p27Kip1, a cell cycle inhibitor, was absent in Sox2-null IPCs. Similarly, upon direct deletion of p27Kip1, p27Kip1-null IPCs also proliferated but retained Sox2 expression. Interestingly, cell cycle control of IPCs by Sox2-mediated expression of p27Kip1 gradually declined with age. In addition, deletion of Sox2 or p27Kip1 did not cause a cell fate change. Finally, chromatin immunoprecipitation with Sox2 antibodies and luciferase reporter assays with the p27Kip1 promoter support that Sox2 directly activates p27Kip1 transcription in postmitotic IPCs. Hence, in contrast to the well-known activity of Sox2 in promoting proliferation and cell fate determination, our data demonstrate that Sox2 plays a novel role as a key upstream regulator of p27Kip1 to maintain the quiescent state of postmitotic IPCs. Our studies suggest that manipulating Sox2 or p27Kip1 expression is an effective approach to inducing proliferation of neonatal auditory IPCs, an initial but necessary step toward restoring hearing in mammals.

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

“…In contrast, downregulation of Notch and Fgf signaling correlates with the downregulation of cdk inhibitors. It is possible that active Notch or Fgf signaling induces cdk inhibitors, causing cells to exit the cell cycle or become quiescent (66). However, manipulation of Notch signaling does not affect the cell cycle in chick or murine inner ears (13,30), suggesting that signaling pathways other than Wnt/β-catenin and Notch are involved in triggering or inhibiting proliferation.…”

Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo

“…Kip1 control of SC proliferation (Liu et al, 2012b). Such an age-dependent decline in the ability to self-repair has been observed in other organ systems: hearts from P1 mice can regenerate after damage and this regenerative capacity is lost in P7 mice (Porrello et al, 2011).…”

Sensory hair cell development and regeneration: similarities and differences

“…In the mature cochlea, the degree of mitotic response was significantly lower than in the neonatal organ (Liu et al, 2012c;Oesterle et al, 2011). These findings suggest that p27 Kip1 also contributes to the mitotic quiescence of supporting cells in the postnatal period.…”

“…Kip1 is acutely ablated in vivo or suppressed in vitro, supporting cells in the neonatal cochlea proliferate but do not acquire a hair cell fate (Liu et al, 2012c;Maass et al, 2013;Oesterle et al, 2011). In the mature cochlea, the degree of mitotic response was significantly lower than in the neonatal organ (Liu et al, 2012c;Oesterle et al, 2011).…”