The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4
The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4
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DOI：
10.1016/j.devcel.2006.07.005
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发表时间：
2006-09-01
影响因子：
11.8
通讯作者：
Constam, Daniel B.
中科院分区：
文献类型：
--
作者：
Ben-Haim, Nadav;Lu, Cindy;Constam, Daniel B.
在小鼠发育早期，枯草杆菌素样原蛋白转换酶(SPC)Furin和PACE4形成原始外胚层和内脏内胚层的模式，推测是通过激活与转化生长因子β相关的Nodal前体。在这里，SPC基序的突变提供了直接证据，表明结节处理是指定前内脏内胚层和中内胚层所必需的。然而，令人惊讶的是，Nodal前体结合并激活激活素受体，以维持在远离Nodal来源的胚胎外胚层中Furin、PACE4和Bmp4的表达。反过来，Bmp4诱导WNT3，WNT3放大了上胚层中Nodal的表达，并介导了中胚层的诱导。我们的结论是，未切割的Nodal维持着胚外原蛋白转换酶和Bmp4的来源，在两个具有双时间尺度的非冗余反馈环中放大Nodal信号，并在后极点定位原始条纹的形成。基于数学模型，我们讨论了这些顺序环路如何控制细胞的命运。
During early mouse development, the subtilisin-like proprotein convertases (SPC) Furin and PACE4 pattern the primitive ectoderm and visceral endoderm, presumably by activating the TGF beta-related Nodal precursor. Here, mutation of the SPC motif provides direct evidence that Nodal processing is essential to specify anterior visceral endoderm and mesendoderm. Surprisingly, however, the Nodal precursor binds and activates activin receptors to maintain expression of Furin, PACE4, and Bmp4 in extraembryonic ectoderm at a distance from the Nodal source. In return, Bmp4 induces Wnt3, which amplifies Nodal expression in the epiblast and mediates induction of mesoderm. We conclude that uncleaved Nodal sustains the extraembryonic source of proprotein convertases and Bmp4 to amplify Nodal signaling in two nonredundant feedback loops with dual timescales and to localize primitive streak formation at the posterior pole. Based on mathematical modeling, we discuss how these sequential loops control cell fate.