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Abstract
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.
ACKNOWLEDGMENTS
We thank T. Kennedy for invaluable advice, M. Busslinger for the pMyc-Gro/TLE4 plasmid, and L. Liu, R. Lo, Y. Tang, and T. Ruiz de Algara for excellent technical assistance.
This study was supported by grants MOP-13957 and MGC-14971 from the Canadian Institutes for Health Research (CIHR) to S.S., who is a Senior Scholar of the Fonds de la Recherche en Sante du Quebec, and by a Genome Canada grant to C.D.H., who is a CIHR New Investigator and a Michael Smith Foundation for Health Research Scholar.