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J. Biol. Chem., Vol. 283, Issue 36, 24881-24888, September 5, 2008

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Inhibition of Cortical Neuron Differentiation by Groucho/TLE1 Requires Interaction with WRPW, but Not Eh1, Repressor Peptides^*

Manuel Buscarlet, Alessandro Perin, Adam Laing, Joshua Mark Brickman¹, and Stefano Stifani²

From the Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada and the Institute for Stem Cell Research, MRC Centre for Regenerative Medicine, King's Buildings, West Mains Road, Edinburgh EH9 3JQ, United Kingdom

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.

Received for publication, January 28, 2008 , and in revised form, June 13, 2008.

^* This work was supported in part by a Residency Fellowship from the University of Padova (Neurosurgical Unit, Treviso Hospital, Treviso, Italy) (to A. P.), an MRC Studentship (to A. L.), by grants from the Wellcome Trust and Scottish Funding Council (to J. M. B.), and the Canadian Institutes of Health Research (MOP-13957) (to S. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A recipient of an MRC Senior Non-Clinical Fellowship.

² A Chercheur National of the Fonds de la Recherche en Sante du Quebec. To whom correspondence should be addressed: Montreal Neurological Institute, 3801 Rue University, Montreal, Quebec H3A2B4, Canada. Fax: 514-398-1319; E-mail: stefano.stifani{at}mcgill.ca.

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