1. The Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation
- Author
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Megan Brewster, Shuxin Li, Tsz Y. Lo, Jessica I. Goldshteyn, Leann Miles, Katarzyna Pogoda, Paul A. Janmey, Dan Li, Jingyun Qiu, Panteleimon Rompolas, Koushik Mandal, Gareth M. Thomas, Qin Wang, Yuanquan Song, Shannon Trombley, Shuchao Wang, Ye He, Chuxi Wang, Feng Li, Jingwen Niu, and Harun N. Noristani
- Subjects
0301 basic medicine ,Cell cycle checkpoint ,DNA damage ,Science ,General Physics and Astronomy ,Cell Cycle Proteins ,Mice, Transgenic ,Ataxia Telangiectasia Mutated Proteins ,Protein Serine-Threonine Kinases ,Molecular neuroscience ,Ion Channels ,Article ,General Biochemistry, Genetics and Molecular Biology ,Animals, Genetically Modified ,03 medical and health sciences ,0302 clinical medicine ,Mechanosensitive ion channel ,Animals ,Drosophila Proteins ,Humans ,CHEK1 ,Regeneration and repair in the nervous system ,Mice, Knockout ,Multidisciplinary ,Mechanosensation ,Chemistry ,Regeneration (biology) ,General Chemistry ,G2-M DNA damage checkpoint ,Neuroregeneration ,Axons ,Cellular neuroscience ,Nerve Regeneration ,Cell biology ,Mice, Inbred C57BL ,Drosophila melanogaster ,HEK293 Cells ,Mechanisms of disease ,030104 developmental biology ,Checkpoint Kinase 1 ,biological phenomena, cell phenomena, and immunity ,030217 neurology & neurosurgery ,Signal Transduction - 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., The Atr-Check1 pathway is involved in cell cycle and the DNA damage response. Here, the authors show that the Atr-Check1 pathway can inhibit axon regeneration in response to Piezo-mediated mechanosensation, affecting functional recovery.
- Published
- 2021