Opposite effects of Activin type 2 receptor ligands on cardiomyocyte proliferation during development and repair.
Opposite effects of Activin type 2 receptor ligands on cardiomyocyte proliferation during development and repair.
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DOI：
10.1038/s41467-017-01950-1
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发表时间：
2017-12-01
影响因子：
16.6
通讯作者：
Reischauer S
中科院分区：
文献类型：
--
作者：
Dogra D;Ahuja S;Kim HT;Rasouli SJ;Stainier DYR;Reischauer S
斑马鱼能非常有效地再生受损的心肌组织。因此，深入了解斑马鱼心脏再生的分子网络可能有助于开发恢复人类心脏功能的替代策略。虽然TGF-β信号转导与斑马鱼心脏再生有关，但其单个配体的作用仍不清楚。在这里，我们报告了两个基因，mstnb和inhbaa，编码TGF-β家族配体在斑马鱼心脏再生过程中的相反表达反应。使用功能获得（GOF）和功能丧失（LOF）的方法，我们表明，这些配体介导心脏再生，特别是心肌细胞（CM）增殖的逆效应。值得注意的是，我们发现Inhbaa作为CM有丝分裂原发挥作用，并且其过表达导致损伤后加速心脏恢复和瘢痕清除。相比之下，mstnb GOF和inhbaa LOF均导致心脏损伤后未解决的瘢痕形成。我们进一步表明，Mstnb和Inhbaa通过交替激活素2型受体反向控制Smad 2和Smad 3转录因子的活性。斑马鱼可以再生受损的心肌组织，但尚不清楚这是如何调节的。在这里，作者表明两个TGF-β家族成员Mstnb和Inhbaa在再生中具有相反的作用，mstnb过表达或inhbaa功能丧失导致损伤后的心脏瘢痕形成。
Zebrafish regenerate damaged myocardial tissue very effectively. Hence, insights into the molecular networks underlying zebrafish heart regeneration might help develop alternative strategies to restore human cardiac performance. While TGF-β signaling has been implicated in zebrafish cardiac regeneration, the role of its individual ligands remains unclear. Here, we report the opposing expression response during zebrafish heart regeneration of two genes, mstnb and inhbaa, which encode TGF-β family ligands. Using gain-of-function (GOF) and loss-of-function (LOF) approaches, we show that these ligands mediate inverse effects on cardiac regeneration and specifically on cardiomyocyte (CM) proliferation. Notably, we find that Inhbaa functions as a CM mitogen and that its overexpression leads to accelerated cardiac recovery and scar clearance after injury. In contrast, mstnb GOF and inhbaa LOF both lead to unresolved scarring after cardiac injury. We further show that Mstnb and Inhbaa inversely control Smad2 and Smad3 transcription factor activities through alternate Activin type 2 receptors. Zebrafish can regenerate damaged myocardial tissue but it is unclear how this is regulated. Here, the authors show that two TGF-β family members, Mstnb and Inhbaa, have opposite effects in regeneration, with mstnb overexpression or inhbaa loss-of-function causing cardiac scarring after injury.
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影响因子：
64.5
作者：
Bersell, Kevin;Arab, Shima;Kuehn, Bernhard
通讯作者：
Kuehn, Bernhard
影响因子：
21.3
作者：
D'Uva, Gabriele;Aharonov, Alla;Tzahor, Eldad
通讯作者：
Tzahor, Eldad
影响因子：
2.7
作者：
Ahuja, Suchit;Dogra, Deepika;Reischauer, Sven
通讯作者：
Reischauer, Sven
影响因子：
3.6
作者：
Jinnin, M;Ihn, H;Tamaki, K
通讯作者：
Tamaki, K
影响因子：
4.8
作者：
Chipuk, JE;Cornelius, SC;Danielpour, D
通讯作者：
Danielpour, D