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Detrimental effects of glucocorticoids on neuronal migration during brain development

Molecular Psychiatry volume 14, pages 1119–1131 (2009)Cite this article

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.

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Acknowledgements

We thank Dr S Furukawa (Gifu Pharmaceutical University) for advice on the in utero electroporation technique. This research was supported by Grant-in-Aids for Scientific Research (20240038) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (KS).

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Authors and Affiliations

  1. Department of Neuroscience (D13), Osaka University Graduate School of Medicine, Osaka, Japan

    K Fukumoto, T Morita, T Mayanagi, D Tanokashira, T Yoshida & K Sobue

  2. Department of Neuropsychiatry, School of Medicine, Iwate Medical University, Iwate, Japan

    K Fukumoto, T Yoshida & A Sakai

  3. The Research Center for Child Mental Development, Osaka University Graduate School of Medicine, Osaka, Japan

    T Mayanagi & K Sobue

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  1. K Fukumoto
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Correspondence to K Sobue.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Fukumoto, K., Morita, T., Mayanagi, T. et al. Detrimental effects of glucocorticoids on neuronal migration during brain development. Mol Psychiatry 14, 1119–1131 (2009). https://doi.org/10.1038/mp.2009.60

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