Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in mice
Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in mice
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DOI：
10.1073/pnas.0907008106
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发表时间：
2009-08-18
影响因子：
11.1
通讯作者：
Cremona, Ottavio
中科院分区：
文献类型：
--
作者：
Chen, Hong;Ko, Genevieve;Cremona, Ottavio
Epsins是内吞衔接子，在网格蛋白介导的内吞作用的一般方面以及在特定膜蛋白的内化中具有推定的功能。我们现在已经通过遗传方法在小鼠中测试了普遍表达的epsin基因Epn 1和Epn 2的作用。虽然任一基因都是终身失活的，但它们的联合失活导致E9.5-E10的胚胎致死，即，在器官形成的初期。与在果蝇中的研究一致，其中epsin内吞功能与Notch激活相关，在epsin 1/2双敲除（DKO）胚胎中观察到的发育缺陷概括了由Notch信号传导的整体损伤产生的发育缺陷。因此，Notch主要靶基因的表达在DKO胚胎中严重降低。然而，管家形式的网格蛋白介导的内吞作用并没有受到损害的细胞来自这些胚胎。这些发现支持epsin作为一种专门的内吞衔接子的作用，在哺乳动物中Notch信号的激活中起关键作用。
Epsins are endocytic adaptors with putative functions in general aspects of clathrin-mediated endocytosis as well as in the internalization of specific membrane proteins. We have now tested the role of the ubiquitously expressed epsin genes, Epn1 and Epn2, by a genetic approach in mice. While either gene is dispensable for life, their combined inactivation results in embryonic lethality at E9.5-E10, i.e., at the beginning of organogenesis. Consistent with studies in Drosophila, where epsin endocytic function was linked to Notch activation, developmental defects observed in epsin 1/2 double knockout (DKO) embryos recapitulated those produced by a global impairment of Notch signaling. Accordingly, expression of Notch primary target genes was severely reduced in DKO embryos. However, housekeeping forms of clathrin-mediated endocytosis were not impaired in cells derived from these embryos. These findings support a role of epsin as a specialized endocytic adaptor, with a critical role in the activation of Notch signaling in mammals.