Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
J Neurosci. 2011 Oct 12;31(41):14794-9. doi: 10.1523/JNEUROSCI.2774-11.2011.
Huntington's disease (HD), caused by an expanded triplet repeat in the huntingtin (Htt) gene, 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 that mitochondria-mediated cell apoptotic processes are involved in the neuronal death. The timing of knockdown 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 whether the loss of wild-type huntingtin function contributes to pathogenesis in Huntington's disease, these results clearly contraindicate the use of nonspecific knockdown of Htt as a therapeutic measure in HD, particularly in utero.
亨廷顿病（HD）是由亨廷顿（Htt）基因中三核苷酸重复扩展引起的，导致广泛的神经病理学改变，但由于基因敲除会导致小鼠胚胎致死，因此通过基因敲除研究 Htt 基因在中枢神经系统发育中的作用存在问题。在这里，我们报告说，神经上皮细胞中海豚基因表达的敲低会导致细胞迁移紊乱、增殖减少和细胞死亡增加，这在早期神经发育中相对特异。然而，在小脑，Htt 敲低会导致细胞死亡而不会干扰迁移。用 Casp9 的共敲低可以部分逆转皮层中的细胞死亡表型，表明线粒体介导的细胞凋亡过程参与了神经元死亡。在早期发育过程中敲低的时间也是一个重要的变量。这些结果表明 Htt 表达在神经发育中存在时空需求。尽管尚不确定野生型亨廷顿蛋白功能的丧失是否会导致亨廷顿病的发病机制，但这些结果清楚地表明，在亨廷顿病中，特别是在子宫内，不建议使用非特异性 Htt 敲低作为治疗措施。
