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The Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation

Author

Listed:
  • Feng Li

    (Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • Tsz Y. Lo

    (Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia)

  • Leann Miles

    (University of Pennsylvania)

  • Qin Wang

    (Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • Harun N. Noristani

    (Temple University School of Medicine
    Temple University School of Medicine)

  • Dan Li

    (Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia)

  • Jingwen Niu

    (Temple University School of Medicine)

  • Shannon Trombley

    (Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia)

  • Jessica I. Goldshteyn

    (Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia)

  • Chuxi Wang

    (Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia)

  • Shuchao Wang

    (Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia)

  • Jingyun Qiu

    (Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia)

  • Katarzyna Pogoda

    (University of Pennsylvania
    Institute of Nuclear Physics, Polish Academy of Sciences)

  • Kalpana Mandal

    (University of Pennsylvania)

  • Megan Brewster

    (University of Pennsylvania)

  • Panteleimon Rompolas

    (University of Pennsylvania)

  • Ye He

    (The City University of New York, Graduate Center - Advanced Science Research Center, Neuroscience Initiative)

  • Paul A. Janmey

    (University of Pennsylvania)

  • Gareth M. Thomas

    (Temple University School of Medicine
    Temple University School of Medicine)

  • Shuxin Li

    (Temple University School of Medicine
    Temple University School of Medicine)

  • Yuanquan Song

    (Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia
    University of Pennsylvania)

Abstract

Atr is a serine/threonine kinase, known to sense single-stranded DNA breaks and activate the DNA damage checkpoint by phosphorylating Chek1, which inhibits Cdc25, causing cell cycle arrest. This pathway has not been implicated in neuroregeneration. We show that in Drosophila sensory neurons removing Atr or Chek1, or overexpressing Cdc25 promotes regeneration, whereas Atr or Chek1 overexpression, or Cdc25 knockdown impedes regeneration. Inhibiting the Atr-associated checkpoint complex in neurons promotes regeneration and improves synapse/behavioral recovery after CNS injury. Independent of DNA damage, Atr responds to the mechanical stimulus elicited during regeneration, via the mechanosensitive ion channel Piezo and its downstream NO signaling. Sensory neuron-specific knockout of Atr in adult mice, or pharmacological inhibition of Atr-Chek1 in mammalian neurons in vitro and in flies in vivo enhances regeneration. Our findings reveal the Piezo-Atr-Chek1-Cdc25 axis as an evolutionarily conserved inhibitory mechanism for regeneration, and identify potential therapeutic targets for treating nervous system trauma.

Suggested Citation

  • Feng Li & Tsz Y. Lo & Leann Miles & Qin Wang & Harun N. Noristani & Dan Li & Jingwen Niu & Shannon Trombley & Jessica I. Goldshteyn & Chuxi Wang & Shuchao Wang & Jingyun Qiu & Katarzyna Pogoda & Kalpa, 2021. "The Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24131-7
    DOI: 10.1038/s41467-021-24131-7
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    Cited by:

    1. Shannon Trombley & Jackson Powell & Pavithran Guttipatti & Andrew Matamoros & Xiaohui Lin & Tristan O’Harrow & Tobias Steinschaden & Leann Miles & Qin Wang & Shuchao Wang & Jingyun Qiu & Qingyang Li &, 2023. "Glia instruct axon regeneration via a ternary modulation of neuronal calcium channels in Drosophila," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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