BMP signaling promotes zebrafish heart regeneration via alleviation of replication stress.

Mohankrishna Dalvoy Vasudevarao, Denise Posadas Pena, Michaela Ihle, Chiara Bongiovanni, Pallab Maity, Dominik Geissler, Hossein Falah Mohammadi, Melanie Rall-Scharpf, Julian Niemann, Mathilda T M Mommersteeg, Simone Redaelli, Kathrin Happ, Chi-Chung Wu, Arica Beisaw, Karin Scharffetter-Kochanek, Gabriele D'Uva, Mona Malek Mohammadi, Lisa Wiesmüller, Hartmut Geiger, Gilbert Weidinger

Institute of Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.Institute of Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany. · pubmed

Paper

Abstract

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.

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Research summary

The paper claims that BMP signaling alleviates replication stress in cardiomyocytes, promoting heart regeneration in zebrafish. This research is relevant as it addresses mechanisms underlying tissue regeneration and replication stress, which are critical factors in aging and longevity.

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