Detrimental effects of glucocorticoids on neuronal migration during brain development
Detrimental effects of glucocorticoids on neuronal migration during brain development
复制标题
DOI：
10.1038/mp.2009.60
复制
发表时间：
2009-12-01
影响因子：
11
通讯作者：
Sobue, K.
中科院分区：
文献类型：
--
作者：
Fukumoto, K.;Morita, T.;Sobue, K.
糖皮质激素是下丘脑-垂体-肾上腺轴最下游的效应器，是应激反应的主要介质之一。事实上，暴露于高水平的应激引发的糖皮质激素对实验动物的异常行为和人类精神疾病的风险相关的大脑发育是有害的。尽管这方面的知识丰富，糖皮质激素对大脑发育的不利影响的细胞和分子机制仍然不清楚。在这里，我们表明，过量的糖皮质激素延缓有丝分裂后神经元的径向迁移在大脑皮层的发展，并确定肌动蛋白调节蛋白，钙调素，作为糖皮质激素的主要目标。钙调素表达的上调是由糖皮质激素受体依赖性转录的CALD 1基因编码钙调素介导的。这种上调的钙调蛋白负控制肌球蛋白II的功能，导致细胞形状和迁移的变化。体内钙调素的消耗损害径向迁移。钙调素的过度表达也会导致皮质发育过程中放射状迁移延迟，这类似于过量糖皮质激素诱导的放射状迁移延迟。我们的结论是，一个适当的范围内的caldesmon表达是至关重要的径向迁移，其过度表达诱导过量的糖皮质激素延缓皮质发育过程中的径向迁移。因此，这项研究提供了一个新的见解糖皮质激素相关的神经发育障碍的潜在机制。Molecular Psychiatry（2009）14，1119-1131; doi：10.1038/mp.2009.60; 2009年6月30日在线发表
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. Molecular Psychiatry (2009) 14, 1119-1131; doi: 10.1038/mp.2009.60; published online 30 June 2009