1. ¹Department of Neuroscience (D13), Osaka University Graduate School of Medicine, Osaka, Japan
2. ²Department of Neuropsychiatry, School of Medicine, Iwate Medical University, Iwate, Japan
3. ³The Research Center for Child Mental Development, Osaka University Graduate School of Medicine, Osaka, Japan

Correspondence: Dr K Sobue, Department of Neuroscience (D13), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Osaka 565-0871, Japan. E-mail: sobue@nbiochem.med.osaka-u.ac.jp

Received 20 February 2009; Revised 30 April 2009; Accepted 27 May 2009; Published online 30 June 2009.

Abstract

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.