The long term goal of this work is to understand molecular mechanisms underlying development of the mammalian central nervous system (CNS). This laboratory is examining the role of the mammalian hairless (hr)gene in neural development, as hr expression is regulated by thyroid hormone in developing rat brain. Thyroid hormone is essential for proper development of the mammalian CNS; inadequate levels of thyroid hormone during development leads to severe deficits in cognitive and motor functions that include mental retardation and ataxia. Thyroid hormone acts through nuclear receptor proteins that regulate the expression of specific target genes. Few target genes have been identified, thus little is known about the mechanism by which thyroid hormone influences CNS development. We have shown that hr expression is highly induced by thyroid hormone, and in addition, that the protein encoded by hr (Hr) interacts with thyroid hormone receptor. Functional studies indicate that Hr is a transcriptional corepressor, suggesting that the in vivo function of Hr is to influence the expression of other thyroid hormone-responsive genes. As a factor that is both regulated by thyroid hormone and interacts with thyroid hormone receptor, Hr is likely a key mediator of thyroid hormone action in the brain. The proposed research examines hr expression and function in the brain. To help elucidate the role of hr in mammalian brain development, the spatial and temporal expression pattern of hr mRNA and protein will be characterized in developing rat brain. The importance of hr for regulating brain development will be determined by examining loss of hr function in vivo, which should result in alteration of brain structure, function or both. To test this, a null allele of hr will be generated by targeted deletion of the hr locus, and the in vivo function of hr will be assessed by examining potential neurological alterations in hr mutant mice. This analysis will include testing the proposal that Hr influences the expression of downstream thyroid hormone-responsive genes in vivo, by examining thyroid hormone-responsive gene expression in hr mutant mice. The mechanism by which Hr mediates transcriptional repression will be determined using in vitro assays. Understanding the function of a thyroid hormone-responsive gene such as hr will help discern the mechanism of thyroid hormone action in brain development. Such information is necessary for understanding how thyroid hormone deficiency causes neurological abnormalities, and may suggest strategies for prevention and/or treatment of neurological disorders caused by other factors.
