Members of the COUP family of orphan nuclear receptors (COUP-TFI, ARP1 and Ear2) play crucial, yet poorly understood roles in fetal development, including neurogenesis and angiogenesis, and in homeostatic regulatory mechanisms in adult organisms. These proteins are generally believed to function as transcriptional repressors in a histone deacetylase-dependent pathway(s). We have recently identified a mechanistically novel pathway of COUP-mediated transcriptional repression that does not involve the action of trichostatin A-sensitive histone deacetylase(s). A key component in this pathway is the action of two novel, tissue-specifically expressed proteins, CTIP1 and CTIP2, both of which are C2H2 zinc finger proteins that interact directly with all COUP family members and recruit the orphan receptors to heterochromatic loci associated with transcriptional silencing. The CTIPs are also DNA binding proteins that repress transcription from CTIP response elements in mammalian cells independently of the COUP proteins. The CTIP proteins are of great biomedical interest not only because of their role in a novel COUP signaling mechanism, as bona fide transcription factors, and because the mouse CTIP1 locus was identified recently as a site of retroviral insertion that results in cellular transformation and leukemogenesis. The long-term goal of this laboratory is to elucidate the biological significance of and mechanisms by which CTIP proteins influence the transcriptional regulatory activity of COUP family members. To advance toward this goal, the objectives of this proposal are: (1) to determine the mechanistic basis for the action of CTIPs in transcriptional repression mediated by COUP family members, and (2) to determine the biological function(s) of the CTIP proteins. These objectives will be achieved in the context of four Specific Aims: (1) to elucidate the molecular basis of ARP1.CTIP1-mediated transcriptional repression, (2) to identify target genes regulated by CTIP proteins, (3) to elucidate the expression pattern of CTIPs in the developing mouse embryo and adult brain, (4) to determine the function of CTIPs in mice The research proposed in this application will have significant, positive effects on human health on two levels. Firstly, this work will expand our understanding of transcriptional repression mediated by the COUP proteins, possibly other members of the nuclear receptor superfamily, and a growing number of other transcription factors that repress transcription through histone deacetylase-independent pathways in health and disease. Secondly, this work will provide the cornerstone for understanding the molecular, cellular and organismal functions of the CTIP proteins, a novel class of transcriptional repressors that appear to play a pivotal role in the regulation of cellular proliferation in specific hematopoietic cell lineages.
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