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

Abstract

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 Ca 2ϩ and calmodulin-activated kinase (Camk4) pathway. Camk4 was regulated directly by T 3 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. (Endocrinology 151: 810-820, 2010)

The plethora of PMCA isoforms: Alternative splicing and differential expression

“…In a detailed study we provided evidence that the expression of CaMKIV is induced by T 3 in a concentration and time dependent manner in a rat fetal telencephalic culture system [62]. These findings have later been supported by similar observations of Liu and Brent in mouse stem cells including the identification of a thyroid hormone receptor recognition sequence in the promoter region of CaMKIV [63] and by the group of Bernal who studied thyroid hormone regulation of gene expression in the developing rat fetal cerebral cortex [64]. Many studies provided evidence that the availability of the thyroid hormone T 3 is absolutely essential for fetal brain development (for recent reviews see [65,66]).…”

Mechanisms of thyroid hormone action

“…The expression of COUP-TF1 blocks TR from binding the TRE, consistent with protection from early T3 stimulation. Calcium calmodulin-dependent kinase IV (CamKIV), a major thyroid hormone target gene in the developing brain, contains a TRE and COUP-TF1 binding site (101). CamKIV is regulated directly by T3 in primary cultured neurons from fetal cortex and promotes the maturation and proliferation of GABAergic interneurons from their precursor cells (102).…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…Microarray analysis, Northern blotting, RT-qPCR, next-generation RNA sequencing, and in situ hybridization have all been used to study T 3 -regulated gene expression in the brain (392,401,479). Protocols for in situ hybridization and IHC have been described (445,(480)(481)(482)(483)(484).…”