Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration.
Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration.
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DOI：
10.1093/jmcb/mjaa046
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发表时间：
2021-04-10
影响因子：
5.5
通讯作者：
Zhong TP
中科院分区：
文献类型：
--
作者：
Peng X;Lai KS;She P;Kang J;Wang T;Li G;Zhou Y;Sun J;Jin D;Xu X;Liao L;Liu J;Lee E;Poss KD;Zhong TP
心脏再生通过预先存在的心肌细胞（CM）的去分化和增殖发生。然而，损伤诱导CM更新的信号传导机制仍不完全清楚。在这里，我们发现，在斑马鱼心脏损伤诱导表达的分泌Wnt抑制剂，包括Dickkopf 1（Dkk 1），Dkk 3，分泌卷曲相关蛋白1（sFrp 1），和sFrp 2，在心脏组织损伤部位附近。通过Dkk 1过表达阻断Wnt活性可增强CM增殖和心脏再生，而Wnt 8信号的异位激活可减弱损伤诱导的CM去分化和增殖。尽管Wnt信号传导在损伤后被抑制，但在心肌伤口边缘中的无序CM肌节处，细胞质β-连环蛋白意外地增加。我们的分析表明，p21激活激酶2（Pak 2）在再生CM时被诱导，在那里它磷酸化细胞质β-连环蛋白的Ser 675，并增加其在分解肌节中的稳定性。心肌特异性诱导磷酸化模拟β-连环蛋白（S675 E）增强CM去分化和肌节解体对损伤的反应。相反，Pak 2激酶活性的失活减少了Ser 675-磷酸化的β-连环蛋白（pS 675-β-连环蛋白），并减弱了CM肌节的解体和去分化。总之，这些发现表明Wnt信号传导抑制和Pak 2/pS 675-β-连环蛋白信号传导的协调通过支持CM去分化和增殖来增强斑马鱼心脏再生。
Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). However, the signaling mechanisms by which injury induces CM renewal remain incompletely understood. Here, we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors, including Dickkopf 1 (Dkk1), Dkk3, secreted Frizzled-related protein 1 (sFrp1), and sFrp2, in cardiac tissue adjacent to injury sites. Experimental blocking of Wnt activity via Dkk1 overexpression enhances CM proliferation and heart regeneration, whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation. Although Wnt signaling is dampened upon injury, the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges. Our analyses indicated that p21-activated kinase 2 (Pak2) is induced at regenerating CMs, where it phosphorylates cytoplasmic β-catenin at Ser 675 and increases its stability at disassembled sarcomeres. Myocardial-specific induction of the phospho-mimetic β-catenin (S675E) enhances CM dedifferentiation and sarcomere disassembly in response to injury. Conversely, inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylated β-catenin (pS675-β-catenin) and attenuates CM sarcomere disorganization and dedifferentiation. Taken together, these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-β-catenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.
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影响因子：
56.9
作者：
Behrens, J;Jerchow, BA;Birchmeier, W
通讯作者：
Birchmeier, W
影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
21.3
作者：
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通讯作者：
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