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

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.

Transducin-like Enhancer of Split-1 (TLE1) Combines with Forkhead Box Protein G1 (FoxG1) to Promote Neuronal Survival

“…Interaction was also observed in HEK293 cells when the two proteins were ectopically expressed (Fig. 6B), as reported by other laboratories (2,20). Interaction is preserved in TLE1(201-770) and TLE1(451-770), suggesting that FoxG1 binds to the carboxylterminal region of TLE1 (Fig.…”

“…The coding sequence of rat AES was amplified from RNA isolated from rats and subcloned into pTarget vector. All other constructs used were described in previous studies: FoxG1 plasmid constructs (17); TLE1 S239A -FLAG, TLE1 S239E -FLAG, and TLE1 S253A -FLAG (19); and Grg6 FLAG (20).…”

“…1). Because Grg6 lacks the Q domain, it cannot heteromerize with TLE1 (20), but because it possesses the region equivalent to the carboxyl-terminal region of TLE1, Grg6 interacts with FoxG1 (20). Overexpression of Grg6 could thus be expected to disrupt TLE1-FoxG1 interaction through the sequestration of FoxG1.…”

The Paired-box Homeodomain Transcription Factor Pax6 Binds to the Upstream Region of the TRAP Gene Promoter and Suppresses Receptor Activator of NF-κB Ligand (RANKL)-induced Osteoclast Differentiation

“…Transcription Factors-Grg proteins lack DNA binding activity of their own but are recruited by a number of different DNA-binding transcription factors (50). Consistent with this finding, the Pax family members have been reported to bind Grg proteins to cooperatively displace a complex of other stimulating factors and result in attenuation of transcription (47).…”

The molecular basis of neurosensory cell formation in ear development: a blueprint for hair cell and sensory neuron regeneration?

“…(78) The bHLH network functions through the DNA targeting and binding affinities of a combinatorial complex of proteins (78) that involve bHLH dimers, (93) transducin-like enhancer of split (Tle, groucho in fly), runt-related transcription factor (Runx), and forkhead box G1 protein (Foxg1). (84,(94)(95)(96) The TLE protein is the central component with binding sites for HES, runt and forkhead proteins and forms the repressor complex that, in general, prevents neurogenesis (Figs 1,3). HESs also exert an additional effect by competing with the activator bHLH proteins for the ubiquitously expressed class I bHLH activator-binding partner (E protein), Tcfe2a (Figs 1,3).…”