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

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, Kalpana Mandal, Megan Brewster, Panteleimon Rompolas, Ye He, Paul A. Janmey, Gareth M. Thomas, Shuxin Li and Yuanquan Song ()
Additional contact information
Feng Li: Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia
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
Harun N. Noristani: 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
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
Shuxin Li: Temple University School of Medicine
Yuanquan Song: Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24131-7

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