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Biochem Biophys Res Commun February 5, 2019; 509 (2): 557-563.
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N-terminal phosphorylation of xHes1 controls inhibition of primary neurogenesis in Xenopus.

Hardwick LJA , Philpott A .

The processes of cell proliferation and differentiation are intimately linked during embryogenesis, and the superfamily of (basic) Helix-Loop-Helix (bHLH) transcription factors play critical roles in these events. For example, neuronal differentiation is promoted by class II bHLH proneural proteins such as Ngn2 and Ascl1, while class VI Hes proteins act to restrain differentiation and promote progenitor maintenance. We have previously described multi-site phosphorylation as a key regulator of tissue specific class II bHLH proteins in all three embryonic germ layers, and this enables coordination of differentiation with the cell cycle. Hes1 homologues also show analogous conserved proline directed kinase sites. Here we have used formation of Xenopus primary neurons to investigate the effects of xHes1 multi-site phosphorylation on both endogenous and ectopic proneural protein-induced neurogenesis. We find that xHes1 is phosphorylated in vivo, and preventing phosphorylation on three conserved SP/TP sites in the N terminus of the protein enhances xHes1 protein stability and repressor activity. Mechanistically, compared to wild-type xHes1, phospho-mutant xHes1 exhibits greater repression of Ngn2 transcription as well as producing a greater reduction in Ngn2 protein stability and chromatin binding. We propose that cell cycle dependent phosphorylation of class VI Hes proteins may act alongside similar regulation of class II bHLH proneural proteins to co-ordinate their activity.

PubMed ID: 30600182
PMC ID: PMC6363968
Article link: Biochem Biophys Res Commun
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: ascl1 hes1 neurod1 neurog2 sox2 tubb2b
GO keywords: neurogenesis

Article Images: [+] show captions
References [+] :
Ali, Cell cycle-regulated multi-site phosphorylation of Neurogenin 2 coordinates cell cycling with differentiation during neurogenesis. 2011, Pubmed, Xenbase