1 research outputs found

    Thyroid hormone regulation of gene expression in the developing rat fetal cerebral cortex: Prominent role of the Ca2+/calmodulin-dependent protein kinase IV pathway

    Get PDF
    11 p., 6 figures, 1 table and references.Thyroid hormones influence brain development through regulation of gene expression mediated by nuclear receptors. Nuclear receptor concentration increases rapidly in the human fetus during the secondtrimester,aperiod of high sensitivity of the brain to thyroidhormones.In the rat, the equivalent period is the last quarter of pregnancy. However, little is known about thyroid hormone action in the fetal brain, and in rodents, most thyroid hormone-regulated genes have been identified during the postnatal period. To identify potential targets of thyroid hormone in the fetal brain,weinduced maternal and fetal hypothyroidism by maternal thyroidectomy followed by antithyroid drug (2-mercapto-1-methylimidazole) treatment. Microarray analysis identified differentially expressed genes in the cerebral cortex of hypothyroid fetuses on d 21 after conception. Gene function analysis revealed genes involved in the biogenesis of the cytoskeleton, neuronal migration and growth,and branching of neurites. Twenty percent of the differentially expressed genes were related to each other centered on the Ca2 and calmodulin-activated kinase (Camk4) pathway.Camk4was regulated directly by T3 in primary cultured neurons from fetal cortex, and the Camk4 protein was also induced by thyroid hormone. No differentially expressed genes were recovered when euthyroid fetuses from hypothyroid mothers were compared with fetuses from normal mothers. Although the resultsdonot rule out a specific contribution from the mother, especially at earlier stages of pregnancy, they indicate that the main regulators of thyroid hormone-dependent, fetal brain gene expression near term are the fetal thyroid hormones.This work was supported by Grants BFU2005-01740, SAF2008-01168, and SAF2006-14068 from the Ministry of Science and Innovation, Spain, by the European Union Integrated Project CRESCENDO (LSHM- CT-2005-018652), and by the Center for Biomedical Research on Rare Diseases (CIBERER). D.D. was supported by the I3P program of the Consejo Superior de Investigaciones Científicas, Spain, and by a postdoctoral fellowship from The Japanese Society for the Promotion of Science. D.N. was supported by a predoctoral fellowship of the Spanish Ministry of Science and Innovation.Peer reviewe
    corecore