Heat shock factor 2 is a stress-responsive mediator of neuronal migration defects in models of fetal alcohol syndrome.
Heat shock factor 2 is a stress-responsive mediator of neuronal migration defects in models of fetal alcohol syndrome.
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DOI：
10.15252/emmm.201303311
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发表时间：
2014-08
影响因子：
11.1
通讯作者：
Mezger V
中科院分区：
文献类型：
--
作者：
El Fatimy R;Miozzo F;Le Mouël A;Abane R;Schwendimann L;Sabéran-Djoneidi D;de Thonel A;Massaoudi I;Paslaru L;Hashimoto-Torii K;Christians E;Rakic P;Gressens P;Mezger V
胎儿酒精谱系障碍(FASD)是导致智力低下的常见原因。然而，孕期饮酒导致大脑发育缺陷的分子机制尚不清楚。我们使用正常和Hsf2缺陷的小鼠和细胞系统来揭示热休克因子2(HSF2)在皮质放射状神经元迁移缺陷中的关键作用，这是胎儿酒精暴露的标志。当胎儿接触酒精时，HSF2是触发HSF1激活的关键，HSF1激活伴随着独特的翻译后修饰，HSF2引导非典型酒精特异性HSF1-HSF2杂合体的形成。这扰乱了HSF2与正常情况下控制神经元迁移的基因中热休克元件(HSE)的体内结合，例如p35或MAP(微管相关蛋白，如Dclk1和DCX)，并改变了它们的表达。在没有HSF2的情况下，迁移缺陷以及基因表达的变化都会减少。因此，HSF2作为胎儿大脑中酒精应激的传感器，在FASD相关的神经元迁移缺陷中起到了中介作用。学科类别发展与分化；神经科学
Fetal alcohol spectrum disorder (FASD) is a frequent cause of mental retardation. However, the molecular mechanisms underlying brain development defects induced by maternal alcohol consumption during pregnancy are unclear. We used normal and Hsf2-deficient mice and cell systems to uncover a pivotal role for heat shock factor 2 (HSF2) in radial neuronal migration defects in the cortex, a hallmark of fetal alcohol exposure. Upon fetal alcohol exposure, HSF2 is essential for the triggering of HSF1 activation, which is accompanied by distinctive post-translational modifications, and HSF2 steers the formation of atypical alcohol-specific HSF1–HSF2 heterocomplexes. This perturbs the in vivo binding of HSF2 to heat shock elements (HSEs) in genes that control neuronal migration in normal conditions, such as p35 or the MAPs (microtubule-associated proteins, such as Dclk1 and Dcx), and alters their expression. In the absence of HSF2, migration defects as well as alterations in gene expression are reduced. Thus, HSF2, as a sensor for alcohol stress in the fetal brain, acts as a mediator of the neuronal migration defects associated with FASD. Subject Categories Development & Differentiation; Neuroscience