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Thyroid Hormone Regulation of Gene Expression in the Developing Rat Fetal Cerebral Cortex: Prominent Role of the Ca²⁺/Calmodulin-Dependent Protein Kinase IV Pathway

Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM) (M.M.B., P.G.-I., G.M.d.E., J.B.), and Center for Biomedical Research on Rare Diseases (CIBERER) (B.M., C.G.-M., G.M.d.E., J.B.), 28029 Madrid, Spain; Bioinformatics Center, Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011 Japan (D.D.); and Instituto de Neurociencias CSIC-Universidad Miguel Hernández (E.A., D.N., P.B.), 03550 Alicante, Spain

Address all correspondence and requests for reprints to: Juan Bernal, Instituto de Investigaciones Biomédicas, Arturo Duperier 4, 28029 Madrid, Spain. E-mail: jbernal{at}iib.uam.es.

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 second trimester, a period of high sensitivity of the brain to thyroid hormones. 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, we induced 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. Camk4 was 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 results do not 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.