Detrimental effects of glucocorticoids on neuronal migration during brain development.
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.
Fukumoto
K
K
Department of Neuroscience (D13), Osaka University Graduate School of Medicine, Osaka, Japan.
Morita
T
T
Mayanagi
T
T
Tanokashira
D
D
Yoshida
T
T
Sakai
A
A
Sobue
K
K
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D003907:Dexamethasone / Q000494:pharmacology*; D000089622:Doublecortin Domain Proteins; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D024462:Myosin Type II / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000378:metabolism
D002148:Calmodulin-Binding Proteins; D000089622:Doublecortin Domain Proteins; D005938:Glucocorticoids; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; C488416:Tubb3 protein, rat; D014404:Tubulin; D049452:Green Fluorescent Proteins; D003907:Dexamethasone; D024462:Myosin Type II; D001973:Bromodeoxyuridine