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

Authors

Feng Li, Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Tsz Y. Lo, Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Leann Miles, The Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA
Qin Wang, Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Harun N. Noristani, Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Temple University School of Medicine, Philadelphia, PA
Dan Li, Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Jingwen Niu, Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Temple University School of Medicine, Philadelphia, PA
Shannon Trombley, Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Jessica I. Goldshteyn, Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Chuxi Wang, Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Shuchao Wang, Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Jingyun Qiu, Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA
Katarzyna Pogoda, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA
Kalpana Mandal, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA
Megan Brewster, Department of Dermatology, University of Pennsylvania, Philadelphia, PA
Panteleimon Rompolas, Department of Dermatology, University of Pennsylvania, Philadelphia, PA
Ye He, CUNY Advanced Science Research CenterFollow
Pau A. Janmey, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA
Gareth M. Thomas, Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Temple University School of Medicine, Philadelphia, PA
Shuxin Li, Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Temple University School of Medicine, Philadelphia, PA
Yuanquan Song, Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PAFollow

Document Type

Article

Publication Date

2021

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.

Comments

This article was originally published in Nature Communications, available at https://doi.org/10.1038/s41467-021-24131-7

This work is distributed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).