BIOLOGICAL OVERVIEW

groucho is a neurogenic gene and member of the Enhancer of split complex (E[spl]-C). While it is ancestrally unrelated to other genes of E(spl)-C, it is a distinct neurogenic gene that happens to occur in the E(spl)-C neighborhood (Schrons, 1992). groucho is named for a mutant that developed an increased number of supraorbital bristles (bristles around the eye), reminiscent of the bushy browed Marx brother (Schrons, 1992). It encodes a nuclear protein expressed ubiquitously in both embryos and imaginal discs, and acts as a transcriptional repressor of several important genes in Drosophila development.

groucho interacts with helix-loop-helix protein Hairy, one of the Enhancer of split complex genes and Deadpan, and thus regulates transcription as a transcriptional corepressor, in partnership with other proteins. Groucho-E(SPL) protein complexes promote epidermal cell fate by repressing transcription of proneural AS-C genes (Paroush, 1994). In wing discs, hedgehog and engrailed are repressed in anterior cells by the activity of Groucho (de Celis, 1995). Thus Groucho, lacking a DNA binding domain, acts as a transcription factor by combining with other transcription factors to form an active complex repressing the transcription of target genes.

A transgenic embryo assay was employed to discover the mode of repression mediated by Hairy. Hairy can act as a dominant repressor capable of functioning over long distances to block multiple enhancers. Hairy is shown to repress a heterologous enhancer, the rhomboid enhancer sequence, when bound 1 kb from the nearest upstream activator. The binding of Hairy to a modified NEE leads to the repression of both the rhomboid and a distintly linked mesoderm-specific enhancer with a synthetic modular promoter. Two models are proposed for Hairy's long distance repressive function. (1) Hairy could recruit a cofactor that mediates repression at a distance. This factor would inhibit specific upstream activators bound within the proximal promoter. (2) Hairy could interact directly with one or more components of the basal transcriptional complex (Barolo, 1997).

How then does Hairy function? Hairy has been shown to interact with the co-repressor protein Groucho through the C-terminal WRPW motif. Gro is not known to bind DNA, but fusions of GRO with heterologous DNA binding domains have revealed that GRO can act as a transcriptional repressor. The Gro protein contains several repeats of a 40-residue motif, termed the WD40 repeat, that is thought to mediate protein-protein interactions. Tup1, a yeast corepressor protein that also contains WD40 repeats, is recruited to DNA by the alpha2 repressor in alpha-type cells for the silencing of alpha-specific genes. Similarly, Hairy may recruit Gro for silencing specific genes in the Drosophila embryo. The yeast mating-type repressors alpha2 and Tup1 have been reported to interact with histones. This observation raises the possibility that Gro mediates transcriptional silencing by influencing chromatin structure (Barolo, 1997)

GENE STRUCTURE

Bases in 5' UTR - 265

Exons - five

Bases in 3' UTR - 1310

PROTEIN STRUCTURE

Amino Acids 719

Structural Domains

Unlike other proteins of the Enhancer of split complex, Groucho has no bHLH domain. It does contain a WD40 domain, generally used in G protein mediated signal transduction as a protein interaction domain (Tata, 1993). Extra sex combs, a member of the Polycomb group, is another Drosophila transcription factor with a WD motif (Sathe, 1995).

Hairy-related proteins are site-specific DNA-binding proteins defined by the presence of both a repressor-specific bHLH DNA binding domain and a carboxyl-terminal WRPW (Trp-Arg-Pro-Trp) motif. These proteins act as repressors by binding to DNA sites in target gene promoters and not by interfering with activator proteins, indicating that these proteins are active repressors that should therefore have specific repression domains. The WRPW motif is a functional transcriptional repression domain sufficient to confer active repression to Hairy-related proteins or a heterologous DNA-binding protein, Ga14. The WRPW motif is sufficient to recruit Groucho or the TLE mammalian homologs to target gene promoters. Groucho and TLE proteins actively repress transcription when directly bound to a target gene promoter. Thus Groucho family proteins are active transcriptional corepressors for Hairy-related proteins and are recruited by the 4-amino acid protein-protein interaction domain, WRPW (Fisher, 1996).

date revised:  3 July 97

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