The long term goal of this work is to understand how gene regulatory networks controlled by hormones regulate developmental and physiological processes. Nuclear receptors mediate the actions of a variety of hormones by activating the expression of specific genes. Some nuclear receptors can also repress transcription by association with corepressors, but less is known about the mechanisms and significance of repression. This study focuses on a novel nuclear receptor corepressor, the protein encoded by the mammalian Hairless (Hr) gene. This laboratory has demonstrated that the Hairless (HR) protein influences the function of multiple nuclear receptors, including thyroid hormone receptors, vitamin D receptor, and an orphan receptor, ROR. HR functions in many tissues, most prominently in skin as mutations in the Hr gene cause (alopecia) hair loss in humans and mice. Our central hypothesis is that HR influences the expression of downstream hormone-responsive genes in vivo, and that the Hr mutant phenotype arises from specific changes in gene expression. One goal of the proposed research is to determine the molecular mechanisms by which HR acts as a transcriptional represser, and will include the identification of specific proteins, including other nuclear receptors, that interact with HR. Defining the signaling pathways influenced by HR will include the identification of specific target genes that are regulated by HR; based on our recent data, candidate target genes include specific inhibitors of Wnt signaling. The Wnt signaling pathway plays an essential role in tissue development and homeostasis, and disruptions in Wnt signaling are associated with cancer. A second goal is to test HR function in vivo using genetically engineered mice. Recent analysis of mice lacking HR expression has revealed a potential role in regulating stem cell differentiation, a model that will be tested using transgenic mice. Defining the role of HR using skin as a model system will provide insight into diverse biological processes, as HR also influences the activity of receptors that mediate brain development, bone formation and mineral metabolism. Nuclear receptors are already successful therapeutic targets for the treatment of diseases such as diabetes. Understanding the molecular pathway of HR corepressor action will help define a specific mechanism of regulating nuclear receptor function, which in turn may reveal potential sites of intervention to treat developmental and physiologic disorders. Hormones regulate biological processes such as growth and development via nuclear receptors. This work will allow us to understand a specific way of regulating nuclear receptor function, which should be useful for designing therapeutic agents for treating developmental and physiologic disorders. ? ? ?