TAp63γ Demethylation Regulates Protein Stability and Cellular Distribution during Neural Stem Cell Differentiation

p63 is a close relative of the p53 tumor suppressor and transcription factor that modulates cell fate. The full-length isoform of p63, containing a transactivation (TA) domain (TAp63) is an essential proapoptotic protein in neural development. The role of p63 in epithelial development is also well established; however, its precise function during neural differentiation remains largely controversial. Recently, it has been demonstrated that several conserved elements of apoptosis are also integral components of cellular differentiation; p53 directly interacts with key regulators of neurogenesis. The aim of this study was to evaluate the role of p63 during mouse neural stem cell (NSC) differentiation and test whether the histone H3 lysine 27-specific demethylase JMJD3 interacts with p63 to redirect NSCs to neurogenesis. Our results showed that JMJD3 and TAp63 gamma are coordinately regulated to establish neural-specific gene expression programs in NSCs undergoing differentiation. JMJD3 overexpression increased TAp63 gamma levels in a demethylase activity-dependent manner. Importantly, overexpression of TAp63 gamma increased beta-III tubulin whereas downregulation of TAp63 gamma by specific p63 siRNA decreased beta-III tubulin. Immunoprecipitation assays demonstrated direct interaction between TAp63 gamma and JMJD3, and modulation of TAp63 gamma methylation status by JMJD3-demethylase activity. Importantly, the demethylase activity of JMJD3 influenced TAp63 gamma protein stabilization and cellular distribution, as well as TAp63 gamma-regulated neurogenesis. These findings clarify the role of p63 in adult neural progenitor cells and reveal TAp63 gamma as a direct target for JMJD3-mediated neuronal commitment.