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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Viable hypomorphic signaling mutant of the Met receptor reveals a role for hepatocyte growth factor in postnatal cerebellar development
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Viable hypomorphic signaling mutant of the Met receptor reveals a role for hepatocyte growth factor in postnatal cerebellar development

机译：Met受体的可行亚型信号突变体揭示了肝细胞生长因子在出生后小脑发育中的作用

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摘要

Cerebellar development occurs mainly postnatally and implies cell proliferation and migration. Hepatocyte growth factor (HGF) and Met are involved in mediating these responses in other tissues and are coexpressed in the cerebellum. Here we show that Met is localized in granule cell precursors and that cultures of these cells respond to HGF with proliferation. To study the role of HGF and Met in the cerebellum in vivo, we produced a viable hypomorphic Met mutant by knocking in the met locus a point mutation to abrogate the receptor Grb2-binding site. A similar mutant was previously described as perinatal lethal. In this "first-generation" knock-in the recombinant locus retained the Neo cassette (Met~(grb2/grb2neo+)). In the knock-in presented here Neo was Loxed and excised by Cre recombinase, which led to higher tissue levels of Met~(grb2) protein, sufficient to rescue viability. In Met~(grb2/grb2neo-) mice the size of the cerebellum was reduced and foliation defects were evident, especially in the central and posterior half of the vermis. Proliferation of granule precursors in vivo was 25% lower than in controls. In cultures of mutant granule cells HGF-induced microtubule-associated protein kinase activation was reduced and transient. Behavioral tests indicated a balance impairment in Met~(grb2/grb2neo-) mice. Altogether these data indicate that normal cerebellar development and, possibly, function, require HGF and Met, and that proliferation of granule cells in the cerebellum critically depends on full HGF/Met signaling.
机译：小脑发育主要发生在出生后，意味着细胞增殖和迁移。肝细胞生长因子（HGF）和Met参与介导其他组织中的这些反应，并在小脑中共表达。在这里，我们显示Met定位于颗粒细胞前体中，这些细胞的培养物对HGF的增殖反应。为了研究HGF和Met在体内小脑中的作用，我们通过敲击相遇的点突变来消除受体Grb2结合位点，从而产生了可行的亚型Met突变体。先前将类似的突变体描述为围产期致死的。在该“第一代”敲入中，重组基因座保留了Neo盒（Met_（grb2 / grb2neo +））。在这里介绍的敲入中，Neo被Cre重组酶固定并切除，导致组织中Met〜（grb2）蛋白水平升高，足以挽救生存力。在Met〜（grb2 / grb2neo-）小鼠中，小脑的大小减小了，并且明显出现了叶状缺陷，特别是在mis骨的中央和后半部。体内颗粒前体的增殖比对照低25％。在突变颗粒细胞的培养物中，HGF诱导的微管相关蛋白激酶激活减少且是瞬时的。行为测试表明Met〜（grb2 / grb2neo-）小鼠的平衡受损。总而言之，这些数据表明正常的小脑发育以及可能的功能需要HGF和Met，并且小脑中的颗粒细胞增殖关键取决于完整的HGF / Met信号传导。

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