Inhibition of cortical astrocyte differentiation by Hes6 requires amino- and carboxy-terminal motifs important for dimerization and phosphorylation.
Hairy/Enhancer of split (Hes) 6 is a basic helix-loop-helix protein that interacts with the transcriptional co-repressor, Groucho, and antagonizes the neural functions of the Notch pathway. More specifically, mouse Hes6 regulates cerebral corticogenesis by promoting neurogenesis and suppressing astrocyte differentiation. The molecular mechanisms underlying the anti-astrogenic function of Hes6 are ... poorly defined. Here we describe studies aimed at testing whether Hes6 inhibits astrocyte differentiation by antagonizing the transcription repression activity of Notch-activated Hes family members like Hes1. It is reported that Hes6 preferentially forms homodimers. Heterodimerization with Hes1 is antagonized in part by a conserved N-terminal patch of negatively charged residues. Mutation of this motif enhances heterodimerization with Hes1 and increases Hes6 ability to antagonize Hes1-mediated transcriptional repression. However, this mutation does not increase, but instead decreases, the anti-astrogenic activity of Hes6. It is shown further that Hes6 harbors a second conserved sequence, a C-terminal SPXXSP motif. This sequence is phosphorylated by the mitogen activated protein kinase pathway and its mutation disrupts the anti-astrogenic activity of Hes6 without affecting its ability to suppress Hes1. Together, these observations suggest that Hes6 homodimers regulate astrocyte differentiation through mechanisms that depend on the phosphorylation of Hes6 C-terminal domain but are independent of its ability to suppress Hes1-mediated transcriptional repression.
Mesh Terms:
Amino Acid Motifs, Animals, Astrocytes, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cells, Cultured, Dimerization, Embryo, Mammalian, Gene Expression Regulation, Humans, Mice, Mutation, Neural Inhibition, Phosphorylation, Protein Structure, Tertiary, Repressor Proteins, Stem Cells, Transcription, Genetic, Transfection
Amino Acid Motifs, Animals, Astrocytes, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cells, Cultured, Dimerization, Embryo, Mammalian, Gene Expression Regulation, Humans, Mice, Mutation, Neural Inhibition, Phosphorylation, Protein Structure, Tertiary, Repressor Proteins, Stem Cells, Transcription, Genetic, Transfection
J Neurochem
Date: Dec. 01, 2007
PubMed ID: 17868320
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