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BMP signaling promotes zebrafish heart regeneration via alleviation of replication stress

Author

Listed:
  • Mohankrishna Dalvoy Vasudevarao

    (Ulm University)

  • Denise Posadas Pena

    (Ulm University)

  • Michaela Ihle

    (Ulm University)

  • Chiara Bongiovanni

    (University of Bologna
    IRCCS Azienda Ospedaliero-Universitaria di Bologna)

  • Pallab Maity

    (Ulm University)

  • Dominik Geissler

    (Ulm University)

  • Hossein Falah Mohammadi

    (Ulm University)

  • Melanie Rall-Scharpf

    (Ulm University)

  • Julian Niemann

    (Ulm University)

  • Mathilda T. M. Mommersteeg

    (University of Oxford)

  • Simone Redaelli

    (University of Zurich)

  • Kathrin Happ

    (Ulm University)

  • Chi-Chung Wu

    (Ulm University)

  • Arica Beisaw

    (Heidelberg University)

  • Karin Scharffetter-Kochanek

    (Ulm University)

  • Gabriele D’Uva

    (University of Bologna
    IRCCS Azienda Ospedaliero-Universitaria di Bologna)

  • Mona Malek Mohammadi

    (University of Bonn)

  • Lisa Wiesmüller

    (Ulm University)

  • Hartmut Geiger

    (Ulm University)

  • Gilbert Weidinger

    (Ulm University)

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.

Suggested Citation

  • Mohankrishna Dalvoy Vasudevarao & Denise Posadas Pena & Michaela Ihle & Chiara Bongiovanni & Pallab Maity & Dominik Geissler & Hossein Falah Mohammadi & Melanie Rall-Scharpf & Julian Niemann & Mathild, 2025. "BMP signaling promotes zebrafish heart regeneration via alleviation of replication stress," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56993-6
    DOI: 10.1038/s41467-025-56993-6
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    References listed on IDEAS

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    2. Johanna Flach & Sietske T. Bakker & Mary Mohrin & Pauline C. Conroy & Eric M. Pietras & Damien Reynaud & Silvia Alvarez & Morgan E. Diolaiti & Fernando Ugarte & E. Camilla Forsberg & Michelle M. Le Be, 2014. "Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells," Nature, Nature, vol. 512(7513), pages 198-202, August.
    3. Jenny Fung Ling Chau & Deyong Jia & Zhongfeng Wang & Zhi Liu & Yuanyu Hu & Xin Zhang & Hao Jia & Keng Po Lai & Wai Fook Leong & Bi Jin Au & Yuji Mishina & Ye-Guang Chen & Christine Biondi & Elizabeth , 2012. "A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response," Nature Communications, Nature, vol. 3(1), pages 1-11, January.
    4. Björn Schumacher & Joris Pothof & Jan Vijg & Jan H. J. Hoeijmakers, 2021. "The central role of DNA damage in the ageing process," Nature, Nature, vol. 592(7856), pages 695-703, April.
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