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BMP signaling promotes zebrafish heart regeneration via alleviation of replication stress
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BMP signaling promotes zebrafish heart regeneration via alleviation of replication stress
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Journal Article
BMP signaling promotes zebrafish heart regeneration via alleviation of replication stress
2025
Overview
In contrast to mammals, adult zebrafish achieve complete heart regeneration via proliferation of cardiomyocytes. Surprisingly, we found that regenerating cardiomyocytes experience DNA replication stress, which represents one reason for declining tissue regeneration during aging in mammals. Pharmacological inhibition of ATM and ATR kinases revealed that DNA damage response signaling is essential for zebrafish heart regeneration. Manipulation of Bone Morphogenetic Protein (BMP)-Smad signaling using transgenics and mutants showed that BMP signaling alleviates cardiomyocyte replication stress. BMP signaling also rescues neonatal mouse cardiomyocytes, human fibroblasts and human hematopoietic stem and progenitor cells (HSPCs) from replication stress. DNA fiber spreading assays indicate that BMP signaling facilitates re-start of replication forks after replication stress-induced stalling. Our results identify the ability to overcome replication stress as key factor for the elevated zebrafish heart regeneration capacity and reveal a conserved role for BMP signaling in promotion of stress-free DNA replication.
Zebrafish show robust heart regeneration after injury. Here they show that zebrafish cardiomyocytes experience replication stress, which BMP signaling alleviates via a conserved mechanism of replication fork restart, suggesting a potential for anti-aging and regenerative therapies.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/100
/ 13/106
/ 13/51
/ 14/19
/ 45/88
/ 64/116
/ Aging
/ Animals
/ Animals, Genetically Modified
/ Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors
/ Ataxia Telangiectasia Mutated Proteins - genetics
/ Ataxia Telangiectasia Mutated Proteins - metabolism
/ Bone Morphogenetic Proteins - genetics
/ Bone Morphogenetic Proteins - metabolism
/ DNA
/ Heart
/ Hematopoietic Stem Cells - metabolism
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Mammals
/ Mice
/ Myocytes, Cardiac - cytology
/ Myocytes, Cardiac - metabolism
/ Neonates
/ Science
/ Stress
