The nuclear receptor superfamily constitutes a class of ligand-dependent transcriptional factors that regulate gene expression during many biological processes. This family includes the steroid hormone and retinoid receptors and orphan receptors for which the ligand is unknown. The activity of these receptors is also relevant to disease since alterations in receptor signaling pathways have been linked to various disease processes. The objective of this study is to identify the biological functions of nuclear orphan receptor RORgamma identified in our laboratory. This includes the identification of its target genes and study of the mechanisms by which RORgamma regulates gene expression. In addition, we like to determine its role in disease and the therapeutic potential of this signaling pathway. RORgamma is able to induce transcriptional activation through its response element in many cell types. ROR gamma interacts with several co-activators including CBP, SRC-1 and RIP-140 as well as co-repressors, such as N-COR. It is likely that these interactions involve two different conformations of RORgamma, a transcriptionally active and inactive one. The regulation of the transition between these two states is being investigated. To study interactions between RORgamma and other nuclear proteins further yeast two-hybrid analysis was performed using RORgamma as bait. This analysis identified a novel gene referred to as Glis-1 encoding a nuclear protein containing five zinc-finger domains. Further characterization of this gene is in progress. Although RORgamma is expressed in several tissues, it is most highly expressed in the thymus suggesting specific roles in thymocyte and immune function. To identify the biological functions of RORgamma mice deficient in RORgamma function were generated using targeted disruption of the RORgamma gene. RORgamma-/- mice lack lymph nodes and manifest changes in thymopoiesis. Thymocytes undergo rapidly apoptosis. The latter appears to be due at least in part to decreased expression of Bcl-XL. Our rersults demonstrate that RORgamma is essential for lymph node organogenesis and plays an important role in thymopoiesis. Our findings support a model in which RORgamma functions as a repressor of apoptosis. Future studies will focus on further analysis of the phenotype of the RORgamma-/- mice.
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