Hes6 promotes cortical neurogenesis and inhibits Hes1 transcription repression activity by multiple mechanisms.
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.
Gratton
Michel-Olivier
MO
Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
Torban
Elena
E
Jasmin
Stephanie Belanger
SB
Theriault
Francesca M
FM
German
Michael S
MS
Stifani
Stefano
S
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology*; D054360:Chemokine CXCL1; D018925:Chemokines / Q000378:metabolism; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005982:Glutathione Transferase / Q000378:metabolism; D018257:Helix-Loop-Helix Motifs; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology*; D010766:Phosphorylation; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D005982:Glutathione Transferase; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D012694:Serine; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C475829:CXCL1 protein, human; C475895:Cxcl1 protein, mouse; C411859:HES6 protein, human; C489734:Hes1 protein, mouse; C486570:Hes6 protein, mouse; C078493:HES1 protein, human