The overall goal of the proposed studies is to understand basic mechanisms of thyroid hormone (T3) action in brain development. Brain development is critically dependent on T3, which promotes axonal maturation, dendritic arborization, synapse formation, myelination, cell proliferation and apoptosis. Thyroid hormone deficiency during neonatal/fetal life results in severe mental retardation (i.e., cretinism). Despite the profound effects of thyroid deficiency, relatively little is known about the molecular mechanisms of T3 action in CMS development. Electrical activity in the CNS promotes the elaboration of axons and dendrites, and is required for the establishment and strengthening of synaptic connections. Thus, both hormones and electrical activity are necessary for normal development of the vertebrate brain. Analysis of the immediate early genes (lEGs) induced by electrical activity and by T3 in the developing CNS suggests overlapping signaling pathways. Earlier we discovered that the transcription factor basic transcription element binding protein (BTEB1) is strongly upregulated during postnatal development in rodent brain. We showed that BTEB1 is directly regulated by T3 and that BTEB1 plays a role in neuronal morphogenesis, stimulating neurite extension and branching. Our findings support the view that BTEB1 is a critical player in T3-dependent neuronal morphogenesis. In addition to hormonal regulation, we recently found that BTEB1 is an activity-regulated gene in the CNS. To elucidate the role that BTEB1 plays in mammalian brain development, we propose to: 1) analyze developmental and hormone-dependent BTEB1 expression in mouse CNS, 2) analyze thyroid regulation of the mouse BTEB1 promoter, and 3) analyze activity-dependent regulation of the mouse BTEB1 gene. This research will provide an important foundation for understanding the molecular basis of T3 action on brain development, and will begin to integrate knowledge of hormone-dependent signaling pathways with electrical activity-dependent pathways. A detailed knowledge of these pathways is necessary for understanding basic neurodevelopmental processes, and may suggest strategies for prevention and/or treatment of neurological disorders caused by disruption of hormone signaling pathways. ? ?
