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Molecular and Cellular Biology, December 2005, p. 10916-10929, Vol. 25, No. 24
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.24.10916-10929.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Antagonistic Effects of Grg6 and Groucho/TLE on the Transcription Repression Activity of Brain Factor 1/FoxG1 and Cortical Neuron Differentiation

Nathalie Marçal,1 Harshila Patel,1 Zhifeng Dong,1 Stephanie Belanger-Jasmin,1 Brad Hoffman,3 Cheryl D. Helgason,3 Jinjun Dang,2 and Stefano Stifani1*

Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec,1 Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada,3 Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee2

Received 9 August 2005/ Accepted 4 October 2005

Groucho (Gro)/TLE transcriptional corepressors are involved in a variety of developmental mechanisms, including neuronal differentiation. They contain a conserved C-terminal WD40 repeat domain that mediates interactions with several DNA-binding proteins. In particular, Gro/TLE1 interacts with forkhead transcription factor brain factor 1 (BF-1; also termed FoxG1). BF-1 is an essential regulator of neuronal differentiation during cerebral cortex development and represses transcription together with Gro/TLE1. Gro/TLE-related gene product 6 (Grg6) shares with Gro/TLEs a conserved WD40 repeat domain but is more distantly related at its N-terminal half. We demonstrate that Grg6 is expressed in cortical neural progenitor cells and interacts with BF-1. In contrast to Gro/TLE1, however, Grg6 does not promote, but rather suppresses, BF-1-mediated transcriptional repression. Consistent with these observations, Grg6 interferes with the binding of Gro/TLE1 to BF-1 and does not repress transcription when targeted to DNA. Moreover, coexpression of Grg6 and BF-1 in cortical progenitor cells leads to a decrease in the number of proliferating cells and increased neuronal differentiation. Conversely, Grg6 knockdown by RNA interference causes decreased neurogenesis. These results identify a new role for Grg6 in cortical neuron development and establish a functional link between Grg6 and BF-1.

* Corresponding author. Mailing address: Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada. Phone: (514) 398-3946. Fax: (514) 398-1319. E-mail: stefano.stifani{at}mcgill.ca.

Molecular and Cellular Biology, December 2005, p. 10916-10929, Vol. 25, No. 24
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.24.10916-10929.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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