Cortical development is a complex process that involves many events including proliferation, cell cycle exit
and differentiation that need to be appropriately synchronized. Neural stem cells (NSCs) isolated from embryonic cortex
are characterized by their ability of self-renewal under continued maintenance of multipotency. Cell cycle progression and
arrest during development is regulated by numerous factors, including cyclins, cyclin dependent kinases and their
inhibitors. In this study, we exogenously expressed the homeodomain transcription factor Pitx2, usually expressed in
postmitotic progenitors and neurons of the embryonic cortex, in NSCs with low expression of endogenous Pitx2. We
found that Pitx2 expression induced a rapid decrease in proliferation associated with an accumulation of NSCs in G1
phase. A search for potential cell cycle inhibitors responsible for such cell cycle exit of NSCs revealed that Pitx2
expression caused a rapid and dramatic (≈20-fold) increase in expression of the cell cycle inhibitor p21 (WAF1/Cip1). In
addition, Pitx2 bound directly to the p21 promoter as assessed by chromatin immunoprecipitation (ChIP) in NSCs.
Surprisingly, Pitx2 expression was not associated with an increase in differentiation markers, but instead the expression of
nestin, associated with undifferentiated NSCs, was maintained. Our results suggest that Pitx2 promotes p21 expression
and induces cell cycle exit in neural progenitors.
Keywords: Neocortex, telencephalon, transcription, chromatin, Pitx, p21Cip1, p27Kip2, p57Kip2, neural progenitors, chromatin immunoprecipitation
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