Prolyl isomerase Pin1 and protein kinase HIPK2 cooperate to promote cortical neurogenesis by suppressing Groucho/TLE:Hes1-mediated inhibition of neuronal differentiation

• Published in: Cell death and differentiation 2014-02, Vol.21 (2), p.321-332
• Main Authors: Ciarapica, R, Methot, L, Tang, Y, Lo, R, Dali, R, Buscarlet, M, Locatelli, F, del Sal, G, Rota, R, Stifani, S
• Format: Article
• Language: English
• Subjects: 631/136/142; 631/378/368; 631/80/86; Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biochemistry; Biomedical and Life Sciences; Carrier Proteins - metabolism; Cell Biology; Cell Cycle Analysis; Cell death; Cell Differentiation - drug effects; Cell Line, Tumor; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - metabolism; HEK293 Cells; Homeodomain Proteins - metabolism; Humans; Kinases; Life Sciences; Mice; Naphthoquinones - pharmacology; Neural Stem Cells - cytology; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Neurogenesis; NIMA-Interacting Peptidylprolyl Isomerase; Original Paper; Peptidylprolyl Isomerase - antagonists & inhibitors; Peptidylprolyl Isomerase - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Proteins; Repressor Proteins - metabolism; Stem Cells; Transcription Factor HES-1; Tretinoin - pharmacology
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2013.160

The Groucho/transducin-like Enhancer of split 1 (Gro/TLE1):Hes1 transcriptional repression complex acts in cerebral cortical neural progenitor cells to inhibit neuronal differentiation. The molecular mechanisms that regulate the anti-neurogenic function of the Gro/TLE1:Hes1 complex during cortical neurogenesis remain to be defined. Here we show that prolyl isomerase Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) and homeodomain-interacting protein kinase 2 (HIPK2) are expressed in cortical neural progenitor cells and form a complex that interacts with the Gro/TLE1:Hes1 complex. This association depends on the enzymatic activities of both HIPK2 and Pin1, as well as on the association of Gro/TLE1 with Hes1, but is independent of the previously described Hes1-activated phosphorylation of Gro/TLE1. Interaction with the Pin1:HIPK2 complex results in Gro/TLE1 hyperphosphorylation and weakens both the transcriptional repression activity and the anti-neurogenic function of the Gro/TLE1:Hes1 complex. These results provide evidence that HIPK2 and Pin1 work together to promote cortical neurogenesis, at least in part, by suppressing Gro/TLE1:Hes1-mediated inhibition of neuronal differentiation.