Extraembryonic proteases regulate Nodal signalling during gastrulation
Extraembryonic proteases regulate Nodal signalling during gastrulation
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DOI：
10.1038/ncb890
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发表时间：
2002-12-01
影响因子：
21.3
通讯作者：
Constam, DB
中科院分区：
文献类型：
--
作者：
Beck, S;Le Good, JA;Constam, DB
在原肠胚形成过程中，一系列诱导性组织相互作用将哺乳动物胚胎中预先存在的极性转化为前后模式。这一过程是由 Nodal 触发的，Nodal 是一种与转化生长因子-β (TFG-β) 相关的蛋白质，在外胚层和内脏内胚层中表达，而其辅助受体 Cripto 在 Nodal 下游被诱导。在这里，我们发现前蛋白转化酶 Spc1 和 Spc4（也分别称为 Furin 和 Pace4）在相邻的胚外外胚层中表达。它们在分泌后刺激 Nodal 成熟，并且是体内 Nodal 信号传导所必需的。剥夺胚外外胚层表型的胚胎外植体 Spc1(-/-)； Spc4(-/-)双突变体的内源性Nodal不能诱导Cripto。但重组成熟的Nodal与未切割的前体不同，可以有效地挽救Cripto表达。 Cripto 也在用骨形态发生蛋白 4 (BMP4) 处理的外植体中表达。这表明Nodal可能通过胚胎中的信号通路和胚胎外外胚层中Bmp4的诱导来诱导Cripto。 Spc1 和 Spc4 的缺乏会影响这两条途径，因为这些蛋白酶也会刺激 Bmp4 的诱导。
During gastrulation, a cascade of inductive tissue interactions converts pre-existing polarity in the mammalian embryo into antero-posterior pattern. This process is triggered by Nodal, a protein related to transforming growth factor-beta (TFG-beta) that is expressed in the epiblast and visceral endoderm, and its co-receptor Cripto, which is induced downstream of Nodal. Here we show that the proprotein convertases Spc1 and Spc4 (also known as Furin and Pace4, respectively) are expressed in adjacent extraembryonic ectoderm. They stimulate Nodal maturation after its secretion and are required in vivo for Nodal signalling. Embryo explants deprived of extraembryonic ectoderm phenocopy Spc1(-/-); Spc4(-/-) double mutants in that endogenous Nodal fails to induce Cripto. But recombinant mature Nodal, unlike uncleaved precursor, can efficiently rescue Cripto expression. Cripto is also expressed in explants treated with bone morphogenetic protein 4 (BMP4). This indicates that Nodal may induce Cripto through both a signalling pathway in the embryo and induction of Bmp4 in the extraembryonic ectoderm. A lack of Spc1 and Spc4 affects both pathways because these proteases also stimulate induction of Bmp4.