title: Inhibition of cortical neuron differentiation by Groucho/TLE1 requires interaction with WRPW, but not Eh1, repressor peptides.
abstract: In both invertebrates and vertebrates, transcriptional co-repressors of the Groucho/transducin-like Enhancer of split (Gro/TLE) family regulate a number of developmental mechanisms, including neuronal differentiation. The pleiotropic activity of Gro/TLE depends on context-specific interactions with a variety of DNA-binding proteins. Most of those factors engage Gro/TLE through two different types of short peptide motifs, the WRP(W/Y) tetrapeptide and the Engrailed homology 1 (Eh1) sequence (FXIXXIL). The aim of this study was to elucidate the contribution of WRP(W/Y) and Eh1 motifs to mammalian Gro/TLE anti-neurogenic activity. Here we describe point mutations within the C-terminal WD40 repeat domain of Gro/TLE1 that do not perturb protein folding but disrupt the ability of Gro/TLE1 to inhibit the differentiation of cerebral cortex neural progenitor cells into neurons. One of those mutations, L743F, selectively blocks binding to Hes1, an anti-neurogenic basic helix-loop-helix protein that harbors a WRPW motif. In contrast, the L743F mutation does not disrupt binding to Engrailed1 and FoxG1, which both contain Eh1 motifs, nor to Tcf3, which binds to the Gro/TLE N terminus. These results demonstrate that the recruitment of transcription factors harboring WRP(W/Y) tetrapeptides is essential to the anti-neurogenic function of Gro/TLE1.
authors.affiliation: Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Manuel
authors.initials: M
authors.lastname: Buscarlet
authors.forename: Alessandro
authors.initials: A
authors.lastname: Perin
authors.forename: Adam
authors.initials: A
authors.lastname: Laing
authors.forename: Joshua Mark
authors.initials: JM
authors.lastname: Brickman
authors.forename: Stefano
authors.initials: S
authors.lastname: Stifani
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D056970:Co-Repressor Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D056970:Co-Repressor Proteins; D018398:Homeodomain Proteins; D010455:Peptides; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C499043:TLE1 protein, human; C434946:Tle1 protein, mouse; C078493:HES1 protein, human