Abstract
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 TAp63γ are coordinately regulated to establish neural-specific gene expression programs in NSCs undergoing differentiation. JMJD3 overexpression increased TAp63γ levels in a demethylase activity-dependent manner. Importantly, overexpression of TAp63γ increased β-III tubulin whereas downregulation of TAp63γ by specific p63 siRNA decreased β-III tubulin. Immunoprecipitation assays demonstrated direct interaction between TAp63γ and JMJD3, and modulation of TAp63γ methylation status by JMJD3-demethylase activity. Importantly, the demethylase activity of JMJD3 influenced TAp63γ protein stabilization and cellular distribution, as well as TAp63γ-regulated neurogenesis. These findings clarify the role of p63 in adult neural progenitor cells and reveal TAp63γ as a direct target for JMJD3-mediated neuronal commitment.
Highlights
The transcription factor p63, member of the p53 family, can be expressed as a full-length isoform containing a transactivation (TA) domain, termed TAp63, or as a truncated isoform that lacks the TA domain, termed DNp63
We have previously demonstrated the involvement of specific apoptosis-related microRNAs and proteins, including p53, caspases and calpains, in mouse neural stem cell (NSC) differentiation, by mechanisms that do not result in cell death [7,8,9,10,11]
This study demonstrates for the first time a role for p63 in adult neural progenitors, directing NSCs to a neuronal phenotype
Summary
The transcription factor p63, member of the p53 family, can be expressed as a full-length isoform containing a transactivation (TA) domain, termed TAp63, or as a truncated isoform that lacks the TA domain, termed DNp63. P63 has been well-established as an important regulator of cell survival and cell death in the nervous system, primarily by acting through the apoptosis machinery [2,3,5] In this respect, we have shown that both TA and DNp63 isoforms are involved in molecular mechanisms associated with Alzheimer’s disease [3]. Restrictive activation and careful regulation will assure differentiation efficiency and avoid cell loss In this regard, we have previously demonstrated the involvement of specific apoptosis-related microRNAs and proteins, including p53, caspases and calpains, in mouse neural stem cell (NSC) differentiation, by mechanisms that do not result in cell death [7,8,9,10,11]. Similar to p53, TAp63 can oligomerize, bind to DNA, transactivate p53 target genes, and induce cell cycle arrest and apoptosis [1,3,17]
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