Normal brain development is critically dependent on thyroid hormone (TH) which influences neuronal maturation, neurite outgrowth, synapse formation and myelination. While we know much about the gross morphological defects of the central nervous system (CNS) and the clinical manifestations that result from fetal and neonatal hypothyroidism (i.e., severe mental retardation--cretinism), very little is known about the molecular mechanisms of TH action in neural development. This lack of information hinders our ability to fully understand normal development of the CNS, the etiology of developmental disorders of the CNS and to develop effective treatments for such disorders. The primary objective of this project is to provide a molecular basis for understanding TH action in brain development by studying the transcriptional regulatory networks induced by the hormone. The effects of TH are mediated by the action of specific nuclear receptors (TRs) that function as ligand-activated transcription factors. In the proposed work, two models for vertebrate neural development, the rat and the frog (Xenopus laevis) will be used to identify and analyze the function of novel TH target genes in the developing brain. We previously isolated cDNAs for 34 TH-response genes from tadpole brain and conducted cross-species hybridizations to identify three similarly- regulated genes in embryonic rat brain. In the proposed work, the regulation of gene expression and the function in neural development of two genes identified by this approach will be studied.
The first aim focuses on the basic transcription element binding protein (BTEB), a GC- box transcription factor whose mRNA levels are strongly regulated by TH in developing rat brain. The regulation of expression of this gene in neural cells will be analyzed at both the transcriptional and posttranscriptional levels.
The second aim will analyze the expression and function in neural development of the HMG-box transcription factor HBP1 which has been shown to interact with members of the retinoblastoma family of growth suppressors and likely plays an important role in cell differentiation. The third and final aim will utilize three other cDNA clones for Xenopus TH-response genes (chosen for their hormonal responsiveness and developmental pattern of expression) to identify other novel hormone-regulated genes in rat brain. These two models provide a powerful, complementary system for identifying and characterizing important neurodevelopmental genetic pathways and thus place us in a unique position to provide a molecular basis for understanding both normal and abnormal neurological development.
| Denver, R J; Ouellet, L; Furling, D et al. (1999) Basic transcription element-binding protein (BTEB) is a thyroid hormone-regulated gene in the developing central nervous system. Evidence for a role in neurite outgrowth. J Biol Chem 274:23128-34 |
