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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >RNA-binding protein Musashi family: Roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation
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RNA-binding protein Musashi family: Roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation

机译：RNA结合蛋白武藏家族：中枢神经系统干细胞和室管膜细胞亚群的作用通过靶向破坏和反义消融揭示

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摘要

Homologues of the Musashi family of RNA-binding proteins are evolutionary conserved across species. In mammals, two members of this family, Musashil (Msi1) and Musashi2 (Msi2), are strongly coexpressed in neural precursor cells, including CNS stem cells. To address the in vivo roles of msi in neural development, we generated mice with a targeted disruption of the gene encoding Msi1. Homozygous newborn mice frequently developed obstructive hydrocephalus with aberrant proliferation of ependymal cells in a restricted area surrounding the Sylvius aqueduct. These observations indicate a vital role for msi1 in the normal development of this subpopulation of ependymal cells, which has been speculated to be a source of postnatal CNS stem cells. On the other hand, histological examination and an in vitro neurosphere assay showed that neither the embryonic CNS development nor the self-renewal activity of CNS stem cells in embryonic forebrains appeared to be affected by the disruption of msi1, but the diversity of the cell types produced by the stem cells was moderately reduced by the msi1 deficiency. Therefore, we performed antisense ablation experiments to target both msi1 and msi2 in embryonic neural precursor cells. Administration of the antisense peptide-nucleotides, which were designed to specifically down-regulate msi2 expression, to msi1~(-/-) CNS stem cell cultures drastically suppressed the formation of neurospheres in a dose-dependent manner. Antisense-treated msi1~(-/-) CNS stem cells showed a reduced proliferative activity. These data suggest that msi1 and msi2 are cooperatively involved in the proliferation and maintenance of CNS stem cell populations.
机译：武藏RNA结合蛋白家族的同源物在物种间是进化保守的。在哺乳动物中，该家族的两个成员，Musashil（Msi1）和Musashi2（Msi2），在包括CNS干细胞在内的神经前体细胞中强烈共表达。为了解决msi在神经发育中的体内作用，我们生成了具有针对性的编码Msi1基因破坏的小鼠。纯合子新生小鼠经常在Sylvius导水管周围的受限区域内发生阻塞性脑积水，并伴有室管膜细胞异常增殖。这些观察结果表明，msi1在室管膜细胞亚群的正常发育中起着至关重要的作用，后者被认为是出生后中枢神经系统干细胞的来源。另一方面，组织学检查和体外神经球试验表明，胚胎前脑中枢神经系统干细胞的发育和中枢神经系统干细胞的自我更新活性似乎都不受msi1破坏的影响，但是细胞类型的多样性msi1缺乏症可适度减少干细胞产生的蛋白。因此，我们进行了反义消融实验，以同时靶向胚胎神经前体细胞中的msi1和msi2。设计用于特异性下调msi2表达的反义肽核苷酸对msi1〜（-/-）CNS干细胞培养物的给药以剂量依赖性方式极大地抑制了神经球的形成。反义处理的msi1〜（-/-）CNS干细胞的增殖活性降低。这些数据表明msi1和msi2协同参与中枢神经系统干细胞群体的增殖和维持。

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