Thyroid hormone action in neural development

The goal of our research is to elucidate the molecular mechanisms by which thyroid hormone regulates specific aspects of neural development. Thyroid hormone is required for brain development; deficiency during neonatal development results in irreversible neurological damage both in humans and experimental animals. The effects of thyroid hormone are mediated through nuclear receptor proteins which function as inducible transcription factors. Thus, thyroid hormone influences development by modulating the transcription of specific target genes in response to hormone binding. Work in my lab has focused on identifying and characterizing the functions of such genes in developing rat brain. We have identified several novel thyroid hormone-responsive (TH-responsive) genes, including the mammalian hairless (hr) gene. Based on its expression and the function of its encoded protein, the hr gene is an excellent candidate for mediating the effects of thyroid hormone on neural development. We have shown that hr expression is highly induced (>10-fold) by thyroid hormone, and expression is developmentally regulated and tissue-restricted. The protein encoded by hr (Hr) is not related to known proteins, but using molecular and biochemical techniques we have shown that Hr functions as a corepressor. Corepressors mediate transcriptional repression by unliganded thyroid hormone receptors, thus Hr influences the activity of the same protein that regulates its expression, forming a novel autoregulatory pathway. Hr-mediated repression likely occurs through associated histone deacetylase activity, as Hr also interacts with histone deacetylases. To define the role of hr in vivo, we have generated a null allele in mice and are currently analyzing the phenotypic consequences of loss of hr function. As both a target gene and a corepressor, Hr is likely a key mediator of thyroid hormone action in the brain. Other studies involve analyzing the expression and function of another novel TH-responsive gene, Synaptotagmin-related gene 1 (Srg1). We also continue to identify additional TH-responsive genes, to define the program of gene expression induced by thyroid hormone in developing brain.