Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development.
Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development.
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DOI：
10.1523/jneurosci.2774-11.2011
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发表时间：
2011-10-12
期刊：
影响因子：
--
通讯作者：
Goldowitz D
中科院分区：
文献类型：
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作者：
Tong Y;Ha TJ;Liu L;Nishimoto A;Reiner A;Goldowitz D
亨廷顿舞蹈病是由亨廷顿蛋白基因（Htt）扩大的三重重复引起的，导致广泛的神经病理学，但通过基因敲除研究Htt基因在中枢神经系统发育中的作用是有问题的，因为敲除会导致小鼠的胚胎致死。在这里，我们报道了新皮层神经上皮细胞中Htt表达的下调导致细胞迁移受到干扰，增殖减少，细胞死亡增加，这是早期神经发育相对特异性的。然而，在小脑中，Htt敲低导致细胞死亡，但不影响迁移。Casp9的共敲低可部分逆转皮层细胞死亡表型，表明线粒体介导的细胞凋亡过程参与了神经元死亡。在早期发育阶段，基因敲除的时间也是一个重要的变量。这些结果表明Htt的表达在神经发育过程中具有一定的时空要求。虽然尚不确定野生型亨廷顿蛋白功能的丧失是否与亨廷顿病的发病机制有关，但这些结果明确禁止将非特异性敲除Htt作为亨廷顿病的治疗措施，特别是在子宫内。
Huntington’s disease, caused by an expanded triplet repeat in the huntingtin gene (Htt), results in extensive neuropathology but study of the Htt gene in CNS development through gene knockout is problematic as the knockout leads to embryonic lethality in mice. Here, we report that the knockdown of Htt expression in neuroepithelial cells of neocortex results in disturbed cell migration, reduced proliferation, and increased cell death that is relatively specific to early neural development. In the cerebellum, however, Htt knockdown results in cell death but not perturbed migration. The cell death phenotype in cortex can be partially reversed with co-knockdown of Casp9, indicating mitochondria-mediated cell apoptotic processes are involved in the neuronal death. The timing of knock-down during early development is also an important variable. These results indicate a spatial and temporal requirement for Htt expression in neural development. Although it is uncertain if the loss of wildtype huntingtin function contributes to pathogenesis in Huntington’s disease, these results clearly contraindicate the use of non-specific knockdown of Htt as a therapeutic measure in HD, particularly in utero.