Detrimental effects of glucocorticoids on neuronal migration during brain development

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 stresstriggered 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.

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

“…A comparison of the GC-regulated gene list in our NPSC cultures (Fig. 4A, set 3) with a subset of these studies that used closely related cell types (i.e., rat neural [25] and oligodendrocyte [26] progenitors; Fig. 4A, set 2) revealed 176 common genes (Fig.…”

“…Furthermore, Cxcr4 was also validated as a differentially regulated gene and is implicated in dopaminergic cell migration (49). GC effects on neural stem cell migration are well documented (25). Therefore, GR signaling mediated by Cav-1 could have a critical impact on the biology and development of NPSCs by regulating the degradation of cell cycle regulators or migration of differentiated cells derived from NPSCs to their final position in the cortex.…”

Sox4-mediated caldesmon expression facilitates skeletal myoblast differentiation

“…Thus, it does not appear that the fibro-type-like promoter sequence is involved in mouse Cald1 gene expression. This was not a major concern for the analysis of HeLa-type promoter activity related to CaD expression because HeLa-type promoter activity is weaker than fibro-type promoter activity in various tissues (Fukumoto et al, 2009;Yano et al, 1995).…”

“…To date, several cis-acting elements such as the CArG box and GRE sequence, which are primarily responsible for the transcription of CALD1, have been identified (Fukumoto et al, 2009;Mayanagi et al, 2008;Momiyama et al, 1998;Yano et al, 1995). These conserved cis-acting elements are located in the fibro-type promoter.…”

“…Two independent CALD1 promoters have been identified in both chickens and humans: gizzard-type and brain-type in chickens and fibro-type and HeLa-type in humans (Hayashi et al, 1992;Yano et al, 1994). The activities of gizzard-type and fibro-type promoters are higher than the activities of brain-type and HeLa-type promoters (Fukumoto et al, 2009;Yano et al, 1995). Therefore, most studies of CALD1 promoter activity and associated transcription factors have focused on the gizzard-type or fibro-type promoter.…”