Role of heat-shock factor 2 in cerebral cortex formation and as a regulator of p35 expression
Role of heat-shock factor 2 in cerebral cortex formation and as a regulator of p35 expression
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DOI：
10.1101/gad.366906
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发表时间：
2006-04-01
影响因子：
10.5
通讯作者：
Mezger, V
中科院分区：
文献类型：
--
作者：
Chang, YH;Östling, P;Mezger, V
热休克因子（HSFs）与多种发育过程有关，但它们在这些过程中的作用机制在很大程度上仍然是个谜。hsf 2基因敲除小鼠表现出配子发生缺陷和以脑室扩大为特征的脑异常。在这里，我们表明，Hsf 2（-/-）大脑皮层显示的表层神经元的错位。HSF 2缺乏导致放射状胶质纤维（迁移神经元的结构向导）和分泌定位信号Reelin的Cajal-Retzius细胞数量减少。因此，我们集中在径向迁移信号通路。Reelin和Dab 1酪氨酸磷酸化水平降低，表明Reelin级联反应在Hsf 2（-/-）皮质中受到影响。p35的表达，细胞周期蛋白依赖性激酶5（Cdk 5）的激活剂，径向迁移必不可少的，是依赖于在获得和功能丧失系统中的HSF 2的量。另一种Cdk 5激活剂p39在Hsf 2（-/-）皮质中显示降低的mRNA水平，其与降低的p35水平一起降低Cdk 5活性。我们证明在体内结合HSF 2的p35启动子，从而确定p35作为第一个靶基因HSF 2在皮质发育。总之，HSF 2影响细胞群体，协助放射状迁移，并直接调节p35的表达，放射状神经元迁移的关键演员。
Heat-shock factors (HSFs) are associated with multiple developmental processes, but their mechanisms of action in these processes remain largely enigmatic. Hsf2-null mice display gametogenesis defects and brain abnormalities characterized by enlarged ventricles. Here, we show that Hsf2(-/-) cerebral cortex displays mispositioning of neurons of superficial layers. HSF2 deficiency resulted in a reduced number of radial glia fibers, the architectural guides for migrating neurons, and of Cajal-Retzius cells, which secrete the positioning signal Reelin. Therefore, we focused on the radial migration signaling pathways. The levels of Reelin and Dab1 tyrosine phosphorylation were reduced, suggesting that the Reelin cascade is affected in Hsf2(-/-) cortices. The expression of p35, an activator of cyclin-dependent kinase 5 (Cdk5), essential for radial migration, was dependent on the amount of HSF2 in gain- and loss-of-function systems. p39, another Cdk5 activator, displayed reduced mRNA levels in Hsf2(-/-) cortices, which, together with the lowered p35 levels, decreased Cdk5 activity. We demonstrate in vivo binding of HSF2 to the p35 promoter and thereby identify p35 as the first target gene for HSF2 in cortical development. In conclusion, HSF2 affects cellular populations that assist in radial migration and directly regulates the expression of p35, a crucial actor of radial neuronal migration.