DAAM1 and DAAM2 are co-required for myocardial maturation and sarcomere assembly.
DAAM1 and DAAM2 are co-required for myocardial maturation and sarcomere assembly.
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DOI：
10.1016/j.ydbio.2015.10.003
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发表时间：
2015-12-01
影响因子：
2.7
通讯作者：
Cohen ED
中科院分区：
文献类型：
--
作者：
Ajima R;Bisson JA;Helt JC;Nakaya MA;Habas R;Tessarollo L;He X;Morrisey EE;Yamaguchi TP;Cohen ED
Wnt配体调节心脏形态发生，但其潜在机制尚不清楚。先前发现两种形成蛋白相关蛋白DAAM 1和2结合Wnt效应子Disheveled。在这里，由于DAAM 1和2成核肌动蛋白和介导Wnt诱导的细胞骨架变化，DAAM 1的一个等位基因被用来破坏其功能，特别是在心肌和调查Wnt相关的途径。纯合子Daam 1条件性敲除（CKO）小鼠存活，但心脏畸形，心脏功能差。在妊娠中期观察到Daam 1 CKO小鼠的缺陷，并与心肌细胞侵入流出道的突起丢失有关。此外，这些小鼠表现出心肌致密化不全（NCM）和心肌细胞极性紊乱。有趣的是，Daam 1 CKO小鼠也是插入破坏Daam 2（DKO）的纯合子，具有更强的NCM，严重降低心脏功能，破坏肌节结构，并增加心肌增殖，这表明DAAM 1和DAAM 2具有冗余功能。虽然RhoA在Daam 1/2 DKO小鼠的心脏中不受影响，但AKT活性低于对照组，这引发了DAAM 1/2是否仅介导Wnt信号传导的问题。因此，将Daam 1-floxed小鼠与Wnt 5a缺失小鼠交配以鉴定遗传相互作用。同样为Wnt 5a无效等位基因杂合子的Daam 1 CKO小鼠的心脏比Daam 1 CKO小鼠具有更强的NCM和更严重的心脏功能丧失，这与DAAM 1和Wnt 5a在共同途径中起作用一致。然而，删除Daam 1进一步破坏了Wnt 5a同源零心脏，表明DAAM 1在心脏发育中也具有Wnt 5a非依赖性作用。
Wnt ligands regulate heart morphogenesis but the underlying mechanisms remain unclear. Two Formin-related proteins, DAAM1 and 2, were previously found to bind the Wnt effector Disheveled. Here, since DAAM1 and 2 nucleate actin and mediate Wnt-induced cytoskeletal changes, a floxed-allele of Daam1 was used to disrupt its function specifically in the myocardium and investigate Wnt-associated pathways. Homozygous Daam1 conditional knockout (CKO) mice were viable but had misshapen hearts and poor cardiac function. The defects in Daam1 CKO mice were observed by mid-gestation and were associated with a loss of protrusions from cardiomyocytes invading the outflow tract. Further, these mice exhibited noncompaction cardiomyopathy (NCM) and deranged cardiomyocyte polarity. Interestingly, Daam1 CKO mice that were also homozygous for an insertion disrupting Daam2 (DKO) had stronger NCM, severely reduced cardiac function, disrupted sarcomere structure, and increased myocardial proliferation, suggesting that DAAM1 and DAAM2 have redundant functions. While RhoA was unaffected in the hearts of Daam1/2 DKO mice, AKT activity was lower than in controls, raising the issue of whether DAAM1/2 are only mediating Wnt signaling. Daam1-floxed mice were thus bred to Wnt5a null mice to identify genetic interactions. The hearts of Daam1 CKO mice that were also heterozygous for the null allele of Wnt5a had stronger NCM and more severe loss of cardiac function than Daam1 CKO mice, consistent with DAAM1 and Wnt5a acting in a common pathway. However, deleting Daam1 further disrupted Wnt5a homozygousnull hearts, suggesting that DAAM1 also has Wnt5a-independent roles in cardiac development.