Smad4 controls signaling robustness and morphogenesis by differentially contributing to the Nodal and BMP pathways.
Smad4 controls signaling robustness and morphogenesis by differentially contributing to the Nodal and BMP pathways.
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DOI：
10.1038/s41467-021-26486-3
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发表时间：
2021-11-04
影响因子：
16.6
通讯作者：
Hill CS
中科院分区：
文献类型：
--
作者：
Guglielmi L;Heliot C;Kumar S;Alexandrov Y;Gori I;Papaleonidopoulou F;Barrington C;East P;Economou AD;French PMW;McGinty J;Hill CS
转录效应因子SMAD4是TGF-β家族信号通路的核心组成部分。然而，它在脊椎动物胚胎发育中的作用仍未得到解决。为了解决这个问题，我们在斑马鱼中删除了Smad4，并研究了这对TGF-β家族形态因子、bmp和Nodal信号传导的影响。我们证明，在缺乏Smad4的情况下，由于BMP信号的丢失，背/腹侧胚胎模式被破坏。然而，出乎意料的是，节点信令被维持，但缺乏鲁棒性。这种独立于smad4的节点信号对于中胚层规范是足够的，但对于最优的内胚层规范是不够的。此外，利用光学投影断层扫描结合3D胚胎形态测量，我们已经生成了BMP形态空间，并证明Smad4突变体在形态学上与BMP信号被遗传/药理学干扰的胚胎无法区分。因此，不同TGF-β家族配体对Smad4信号转导的要求是不同的，这对Smad4突变或缺失的疾病有影响。转录效应因子SMAD4在脊椎动物胚胎发育中的作用尚不清楚。作者表明，在缺少Smad4的情况下，由于BMP信号的缺失，背/腹侧胚胎模式被破坏，而节点信号被维持，但不足以实现最佳的内胚层规范。
The transcriptional effector SMAD4 is a core component of the TGF-β family signaling pathways. However, its role in vertebrate embryo development remains unresolved. To address this, we deleted Smad4 in zebrafish and investigated the consequences of this on signaling by the TGF-β family morphogens, BMPs and Nodal. We demonstrate that in the absence of Smad4, dorsal/ventral embryo patterning is disrupted due to the loss of BMP signaling. However, unexpectedly, Nodal signaling is maintained, but lacks robustness. This Smad4-independent Nodal signaling is sufficient for mesoderm specification, but not for optimal endoderm specification. Furthermore, using Optical Projection Tomography in combination with 3D embryo morphometry, we have generated a BMP morphospace and demonstrate that Smad4 mutants are morphologically indistinguishable from embryos in which BMP signaling has been genetically/pharmacologically perturbed. Smad4 is thus differentially required for signaling by different TGF-β family ligands, which has implications for diseases where Smad4 is mutated or deleted. The role of the transcriptional effector SMAD4 in vertebrate embryo development remains unresolved. Here the authors show that in the absence of Smad4, dorsal/ventral embryo patterning is disrupted due to the loss of BMP signaling, while Nodal signaling is maintained, but insufficient for optimal endoderm specification.
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影响因子：
3.6
作者：
Byfield, SD;Major, C;Roberts, AB
通讯作者：
Roberts, AB
影响因子：
2.4
作者：
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Constam, Daniel B.
影响因子：
64.5
作者：
David CJ;Huang YH;Chen M;Su J;Zou Y;Bardeesy N;Iacobuzio-Donahue CA;Massagué J
通讯作者：
Massagué J
影响因子：
4.6
作者：
Dougan, ST;Warga, RM;Talbot, WS
通讯作者：
Talbot, WS