Wnt5a and Wnt11 are essential for second heart field progenitor development
Wnt5a and Wnt11 are essential for second heart field progenitor development
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DOI：
10.1242/dev.069377
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发表时间：
2012-06-01
期刊：
影响因子：
4.6
通讯作者：
Morrisey, Edward E.
中科院分区：
文献类型：
--
作者：
Cohen, Ethan David;Miller, Mayumi F.;Morrisey, Edward E.
Wnt/β-连环蛋白对心脏发生具有双相作用，促进心脏祖细胞的诱导，但随后抑制其分化。β-连环蛋白的缺失抑制第二心脏区域祖细胞和第二心脏区域转录因子Islet 1的表达，表明Wnt/β-连环蛋白信号传导对于第二心脏区域发育是必需的。然而，表达具有组成性活性的β-连环蛋白与Islet 1-Cre也抑制内源性Islet 1表达，反映了延长的Wnt/β-连环蛋白信号传导对第二心脏区域发育的抑制作用。我们发现，两个非典型的Wnt配体，Wnt 5a和Wnt 11，共同需要调节小鼠第二心脏领域的发展。Wnt 5a和Wnt 11的缺失导致发育中的心脏中第二心脏场祖细胞的急剧丧失。重要的是，这种Wnt 5a和Wnt 11的丢失伴随着Wnt/β-连环蛋白信号的增加，并且异位Wnt 5a/Wnt 11抑制β-连环蛋白信号并促进分化的胚胎干细胞中的心脏祖细胞发育。这些数据表明，Wnt 5a和Wnt 11是第二心脏场祖细胞对Wnt/β-连环蛋白信号传导的反应的重要调节剂，并且它们在心脏发育期间通过抑制Wnt/β-连环蛋白信号传导而起作用。
Wnt/beta-catenin has a biphasic effect on cardiogenesis, promoting the induction of cardiac progenitors but later inhibiting their differentiation. Second heart field progenitors and expression of the second heart field transcription factor Islet1 are inhibited by the loss of beta-catenin, indicating that Wnt/beta-catenin signaling is necessary for second heart field development. However, expressing a constitutively active beta-catenin with Islet1-Cre also inhibits endogenous Islet1 expression, reflecting the inhibitory effect of prolonged Wnt/beta-catenin signaling on second heart field development. We show that two non-canonical Wnt ligands, Wnt5a and Wnt11, are co-required to regulate second heart field development in mice. Loss of Wnt5a and Wnt11 leads to a dramatic loss of second heart field progenitors in the developing heart. Importantly, this loss of Wnt5a and Wnt11 is accompanied by an increase in Wnt/beta-catenin signaling, and ectopic Wnt5a/Wnt11 inhibits beta-catenin signaling and promotes cardiac progenitor development in differentiating embryonic stem cells. These data show that Wnt5a and Wnt11 are essential regulators of the response of second heart field progenitors to Wnt/beta-catenin signaling and that they act by restraining Wnt/beta-catenin signaling during cardiac development.