Lorincz Matthew T, Zawistowski Virginia A
Department of Neurology, University of Michigan School of Medicine, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-2200, USA.
Mol Cell Neurosci. 2009 Jan;40(1):1-13. doi: 10.1016/j.mcn.2008.06.004. Epub 2008 Jun 19.
Huntington's disease is an uncommon autosomal dominant neurodegenerative disorder caused by expanded polyglutamine repeats. Increased neurogenesis was demonstrated recently in Huntington's disease post-mortem samples. In this manuscript, neuronally differentiated embryonic stem cells with expanded CAG repeats in the murine Huntington's disease homologue and neural progenitors isolated from the subventricular zone of an accurate mouse Huntington's disease were examined for increased neurogenesis. Embryonic stem cells with expanded CAG repeats in the murine Huntington's disease homologue were demonstrated to undergo facilitated differentiation first into neural progenitors, then into more mature neurons. Neural progenitor cells isolated from the subventricular zone of a Huntington's disease knock-in animal displayed increased production of neural progenitors and increased neurogenesis. These findings suggested that neuronally differentiating embryonic stem cells with expanded CAG repeats is a reasonable system to identify factors responsible for increased neurogenesis in Huntington's disease. Expression profiling analysis comparing neuronally differentiating embryonic stem cells with expanded CAG repeats to neuronally differentiating embryonic stem cells without expanded CAG repeats identified transcripts involved in development and transcriptional regulation as factors possibly mediating increased neurogenesis in response to expanded CAG repeats.
亨廷顿舞蹈症是一种由多聚谷氨酰胺重复序列扩增引起的罕见常染色体显性神经退行性疾病。最近在亨廷顿舞蹈症的尸检样本中发现了神经发生增加的现象。在本论文中，对小鼠亨廷顿舞蹈症同源物中CAG重复序列扩增的神经元分化胚胎干细胞以及从精确的小鼠亨廷顿舞蹈症模型脑室下区分离出的神经祖细胞进行了神经发生增加情况的检测。结果表明，小鼠亨廷顿舞蹈症同源物中CAG重复序列扩增的胚胎干细胞首先经历促进分化成为神经祖细胞，然后再分化为更成熟的神经元。从亨廷顿舞蹈症基因敲入动物的脑室下区分离出的神经祖细胞显示出神经祖细胞产量增加以及神经发生增加。这些发现表明，CAG重复序列扩增的神经元分化胚胎干细胞是鉴定亨廷顿舞蹈症中神经发生增加相关因子的合理系统。通过表达谱分析，将CAG重复序列扩增的神经元分化胚胎干细胞与无CAG重复序列扩增的神经元分化胚胎干细胞进行比较，确定了参与发育和转录调控的转录本，这些转录本可能是介导CAG重复序列扩增导致神经发生增加的因子。
