Opposite effects of Activin type 2 receptor ligands on cardiomyocyte proliferation during development and repair

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-beta 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-beta 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.