Detrimental effects of glucocorticoids on neuronal migration during brain development

• Published in: Molecular psychiatry Vol. 14; no. 12; pp. 1119 - 1131
• Main Authors: Fukumoto, K, Morita, T, Mayanagi, T, Tanokashira, D, Yoshida, T, Sakai, A, Sobue, K
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2009
• Subjects: Actin; Age Factors; Amino acids; Animals; Animals, Newborn; Bromodeoxyuridine - metabolism; Calmodulin-Binding Proteins - genetics; Calmodulin-Binding Proteins - metabolism; Cell migration; Cell Movement - drug effects; Cell size; Cell Size - drug effects; Cells, Cultured; Cerebral cortex; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - growth & development; Cerebral Cortex - pathology; Complications and side effects; Corticosteroids; Dexamethasone - pharmacology; Embryo, Mammalian; Embryonic Stem Cells - drug effects; Female; Gene Expression Profiling - methods; Gene Expression Regulation, Developmental - drug effects; Glucocorticoids; Glucocorticoids - pharmacology; Green Fluorescent Proteins - genetics; Health aspects; Humans; Hypothalamus; Medicine; Mental disorders; MicroRNAs; Microtubule-Associated Proteins - metabolism; Mimicry; Molecular modelling; Mutation; Myosin; Myosin Type II - genetics; Myosin Type II - metabolism; Nervous system diseases; Neurodevelopmental disorders; Neurons - drug effects; Neuropeptides - metabolism; Neurosciences; Oligonucleotide Array Sequence Analysis - methods; Pituitary; Plasmids; Pregnancy; Prenatal Exposure Delayed Effects - chemically induced; Prenatal Exposure Delayed Effects - pathology; Prenatal Exposure Delayed Effects - physiopathology; Rats; Risk factors; Thyroid gland; Time Factors; Transcription; Transfection - methods; Tubulin - metabolism; University graduates; Japan; United States > US
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2009.60

Glucocorticoids, the most downstream effectors of the hypothalamus-pituitary-adrenal axis, are one of main mediators of the stress reaction. Indeed, exposure to high levels of stress-triggered glucocorticoids is detrimental to brain development associated with abnormal behaviors in experimental animals and the risk of psychiatric disorders in humans. Despite the wealth of this knowledge, the cellular and molecular mechanisms underlying the detrimental effects of glucocorticoids on brain development remain unclear. Here, we show that excess glucocorticoids retard the radial migration of post-mitotic neurons during the development of the cerebral cortex, and identify an actin regulatory protein, caldesmon, as the glucocorticoids' main target. The upregulation of caldesmon expression is mediated by glucocorticoid receptor-dependent transcription of the CALD1 gene encoding caldesmon. This upregulated caldesmon negatively controls the function of myosin II, leading to changes in cell shape and migration. The depletion of caldesmon in vivo impairs radial migration. The overexpression of caldesmon also causes delayed radial migration during cortical development, mimicking the excessive glucocorticoid-induced retardation of radial migration. We conclude that an appropriate range of caldesmon expression is critical for radial migration, and that its overexpression induced by excess glucocorticoid retards radial migration during cortical development. Thus, this study provides a novel insight into the underlying mechanism of glucocorticoid-related neurodevelopmental disorders.