I. The developmental biology of leptin and leptin receptors
II. Epigenetic programming by exposure to glucocorticoids early in life
III. Molecular mechanisms of gene regulation by thyroid hormone and corticosteroid receptors during mouse and frog brain development
IV. Neuroendocrine mechanisms of developmental plasticity
V. Structural and functional evolution of the corticotropin releasing-factor family of neuropeptides
VI. Molecular basis for hormone action in amphibian metamorphosis
III. Molecular mechanisms of gene regulation by thyroid hormone and corticosteroid receptors during mouse and frog brain development.The goal of the these studies is to understand basic mechanisms of thyroid hormone (T3) and glucocorticoid (GC) action in brain development and plasticity. 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 CNS development. Stress and stress hormones can have profound and complex effects on brain function and morphology, and consequently on learning, memory, and behavior. We discovered that the Krüppel-like factor 9 (Klf9) is strongly upregulated during postnatal development in frog and rodent brain. We showed that Klf9 is directly regulated by T3 and that Klf9 plays a role in neuronal morphogenesis, stimulating neurite extension and branching. Our findings support the view that Klf9 is a critical player in T3-dependent neuronal morphogenesis. In addition to T3 regulation, we recently found that Klf9 is directly regulated by the stress hormone corticosterone, and that Klf9 is synergistically activated by T3 and corticosterone. We identified regions of the frog and mouse Klf9 genes that support synergistic gene activation, and we are now studying the molecular basis for this synergy. Synergistic gene regulation by TH and CS may be a general, and important phenomenon in animal development. We are also investigating the molecular and cellular mechanisms by which Klf9 influences neuronal morphogenesis.
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