Growth differentiation factor 11 signals through the transforming growth factor-β receptor ALK5 to regionalize the anterior-posterior axis
Growth differentiation factor 11 signals through the transforming growth factor-β receptor ALK5 to regionalize the anterior-posterior axis
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DOI：
10.1038/sj.embor.7400752
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发表时间：
2006-08-01
期刊：
影响因子：
7.7
通讯作者：
Ibanez, Carlos F.
中科院分区：
文献类型：
--
作者：
Andersson, Olov;Reissmann, Eva;Ibanez, Carlos F.
生长分化因子11（Growth differentiation factor 11，GDF 11）通过调控Hox基因的表达，参与小鼠胚胎沿着前后轴的区域化。在胚胎发生过程中介导GDF 11信号传导的受体的身份仍不清楚。在这里，我们表明GDF 11可以与I型受体ALK 4，ALK 5和ALK 7相互作用，但主要使用ALK 4和ALK 5来激活Smad 3依赖性报告基因。Alk 5突变体胚胎在前后图案中显示出畸形，包括缺乏后决定簇Hoxc 10的表达，这类似于Gdf 11无效突变体中发现的缺陷。在Acvr 2b（-/-）背景下，Alk 5中的杂合突变而不是Alk 4或Alk 7中的杂合突变增强了脊椎、肾脏和腭发育中的Gdf 11（-/-）样表型，表明两个受体基因之间存在遗传相互作用。因此，转化生长因子-β（TGF-β）受体ALK 5（迄今为止仅与TGF-β 1至TGF-β 3蛋白的生物学功能相关）在胚胎发生期间介导GDF 11信号传导。
Growth differentiation factor 11 (GDF11) contributes to regionalize the mouse embryo along its anterior-posterior axis by regulating the expression of Hox genes. The identity of the receptors that mediate GDF11 signalling during embryogenesis remains unclear. Here, we show that GDF11 can interact with type I receptors ALK4, ALK5 and ALK7, but predominantly uses ALK4 and ALK5 to activate a Smad3-dependent reporter gene. Alk5 mutant embryos showed malformations in anterior-posterior patterning, including the lack of expression of the posterior determinant Hoxc10, that resemble defects found in Gdf11-null mutants. A heterozygous mutation in Alk5, but not in Alk4 or Alk7, potentiated Gdf11(-/-)-like phenotypes in vertebral, kidney and palate development in an Acvr2b(-/-) background, indicating a genetic interaction between the two receptor genes. Thus, the transforming growth factor-beta (TGF-beta) receptor ALK5, which until now has only been associated with the biological functions of TGF-beta 1 to TGF-beta 3 proteins, mediates GDF11 signalling during embryogenesis.