Academic journal article Genetics

Developmental Roles of the Mi-2/NURD-Associated Protein P66 in Drosophila

Academic journal article Genetics

Developmental Roles of the Mi-2/NURD-Associated Protein P66 in Drosophila

Article excerpt

ABSTRACT

The NURD and Sin3 histone deacetylase complexes are involved in transcriptional repression through global deacetylation of chromatin. Both complexes contain many different components that may control how histone deacetylase complexes are regulated and interact with other transcription factors. In a genetic screen for modifiers of wingless signaling in the Drosophila eye, we isolated mutations in the Drosophila homolog of p66, a protein previously purified as part of the Xenopus NURD/Mi-2 complex. p66 encodes a highly conserved nuclear zinc-finger protein that is required for development and we propose that the p66 protein acts as a regulatory component of the NURD complex. Animals homozygous mutant for p66 display defects during metamorphosis possibly caused by misregulation of ecdysone-regulated expression. Although heterozygosity for p66 enhances a wingless phenotype in the eye, loss-of-function clones in the wing and the eye discs do not have any detectable phenotype, possibly due to redundancy with the Sin3 complex. Overexpression of p66, on the other hand, can repress wingless-dependent phenotypes. Furthermore, p66 expression can repress multiple reporters in a cell culture assay, including a Wnt-responsive TCF reporter construct, implicating the NURD complex in repression of Wnt target genes. By co-immunoprecipitation, p66 associates with dMi-2, a known NURD complex member.

A key event in most signal transduction pathways is the activation or repression of target genes in the nucleus by transcriptional regulators. In recent years, it has become evident that these transcription factors interact with chromatin and that regulation of chromatin structure plays an important role in controlling gene expression. One important mechanism for regulating chromatin structure involves histone acetylation/deacetylation. Histone acetylases are implicated in transcriptional activation while histone deacetylases are involved in repression (KADOSH and STRUHL 1998; Kuo et al. 1998; WANG étal 1998).

One of the major histone deacetylase (HDAC) complexes is the NURD complex (reviewed in AHRINGER 2000). The complex has been purified from mammalian and Xenopus cells and homologs have been identified in Caenorhabditis elegans, Arabidopsis, and Drosophila, suggesting that the complex is conserved throughout plants and animals (ToNG et al. 1998; WADE et al. 1998; XUE et al. 1998; ZHANG et al. 1998, 1999; AHRINGER 2000). The NURD complex is ^2 MD in size and is composed of eight proteins (reviewed in AHRINGER 2000; NG and BIRD 2000). The histone deacetylases HDACl and HDAC2 and two histone-binding proteins, RbAp48 and RbAp46, are found in the NURD complex as well as in the other predominant cellular HDAC complex, the Sin3 complex. In addition to these proteins, the other proposed members of the NURD complex are Mi-2, MBD3, MTAl, and p66 (ToNG et al 1998; WADE et al 1998, 1999; XUE et al 1998; ZHANG et al 1998, 1999; BRACKERTZ et al 2002; FENG étal 2002).

Recently, there has been evidence that the NURD complex is involved in a variety of developmental functions. These include embryonic patterning in Drosophila, C. elegans, and mice, repression by Polycomb proteins in Drosophila, and repression in mouse T-cell development (AHRINGER 2000). The NURD complex as well as the Sin3 complex has also been implicated in repression by unliganded nuclear hormone receptors (HEINZEL et al 1997; XUE et al 1998). In chromatin immunoprecipitation assays, both the Sin3 and the NURD complex were found to be associated with the Xenopus thyroid hormone receptor (TR) β A gene promoter region, suggesting that they could function redundantly to repress transcription (Li et al 2002). In Drosophila, dSin3A regulates transcription mediated by the ecdysone nuclear hormone receptor (EcR), but there are no data implicating the NURD complex in regulation of ecdysone responses (TsAi et al. 1999).

The NURD complex has also been implicated in Wnt signaling in Drosophila where it may be involved in repression by TCF. …

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