The long term goal of his project is to understand the molecular mechanisms underlying the development of the mammalian central nervous system. Many physiological factors influence the development of the central nervous system. Among these factors, thyroid hormones are known to be absolutely essential for proper development. The actions of thyroid hormones are mediated through nuclear receptors, which regulate the expression of specific target genes in response to hormone binding. However, the genes that are regulated by thyroid hormones in the developing brain are largely unknown. The main objective of this proposal is to identify the targets of thyroid hormone receptor action in the brain during a time frame that is critical for proper development. Target genes will be isolate using subtractive hybridization coupled with polymerase chain reaction amplification to identify genes that are expressed in euthyroid but not hypothyroid animals. These genes will then be characterized with respect to their patterns of expression and nucleotide sequence. Using a molecular approach to focus on a class of genes that are likely to be important for central nervous system development will significantly advance our understanding of the effects of differential gene expression on the developing nervous system. The identification and isolation of thyroid hormone responsive genes, coupled with characterization of the proteins they encode, is an essential first step in realizing the ultimate goals of this proposal.
