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Abstract
Hes1 is a mammalian basic helix-loop-helix transcriptional repressor that inhibits neuronal differentiation together with corepressors of the Groucho (Gro)/Transducin-like Enhancer of split (TLE) family. The interaction of Hes1 with Gro/TLE is mediated by a WRPW tetrapeptide present in all Hairy/Enhancer of split (Hes) family members. In contrast to Hes1, the related protein Hes6 promotes neuronal differentiation. Little is known about the molecular mechanisms that underlie the neurogenic activity of Hes6. It is shown here that Hes6 antagonizes Hes1 function by two mechanisms. Hes6 inhibits the interaction of Hes1 with its transcriptional corepressor Gro/TLE. Moreover, it promotes proteolytic degradation of Hes1. This effect is maximal when both Hes1 and Hes6 contain the WRPW motif and is reduced when Hes6 is mutated to eliminate a conserved site (Ser183) that can be phosphorylated by protein kinase CK2. Consistent with these findings, Hes6 inhibits Hes1-mediated transcriptional repression in cortical neural progenitor cells and promotes the differentiation of cortical neurons, a process that is normally inhibited by Hes1. Mutation of Ser183 impairs the neurogenic ability of Hes6. Taken together, these findings clarify the molecular events underlying the neurogenic function of Hes6 and suggest that this factor can antagonize Hes1 activity by multiple mechanisms.
ACKNOWLEDGMENTS
We thank R. St.-Arnaud for reagents, R. Lo and K. Joachim for excellent technical assistance, S. Morris for help and suggestions, R. Bremner for constructive comments, and H. Nuthall, W. Song, and J. Nadeau for help during this work.
These studies were supported by grants from the Canadian Institutes of Health Research (CIHR) (MOP-13957 and GR-14971) to S.S. E.T. was supported by an MNI JTC Fellowship and is a CIHR Fellow. F.M.T. is supported by a studentship from the Fonds de la Recherche en Sante du Quebec (FRSQ). S.S. is an FRSQ Senior Scholar.