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Updated: Nov 1, 2025
One-channel Cell-attached Patch-clamp Recording
Published on: June 9, 2014
The Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation
Feng Li1,2, Tsz Y Lo1, Leann Miles3
1Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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.
Insights
Inhibiting the Atr-Chek1 pathway promotes nerve regeneration and recovery after injury. This conserved mechanism, involving Piezo and NO signaling, offers therapeutic targets for nervous system trauma.
Area of Science:
- Neurobiology
- Molecular Biology
- Cellular Biology
Background:
- The ATR (Ataxia Telangiectasia and Rad3-related) kinase pathway is crucial for sensing DNA damage and activating cell cycle checkpoints.
- This pathway, involving Chek1 (Checkpoint Kinase 1) and Cdc25 (Cell Division Cycle 25), typically leads to cell cycle arrest.
- The role of the ATR-Chek1-Cdc25 pathway in neuroregeneration has not been previously established.
Purpose of the Study:
- To investigate the role of the ATR-Chek1-Cdc25 pathway in neuronal regeneration.
- To identify novel therapeutic targets for enhancing recovery from central nervous system (CNS) injury.
Main Methods:
- Utilized Drosophila sensory neurons to study regeneration.
- Employed genetic manipulations including gene knockout (Atr, Chek1) and overexpression (Cdc25).
- Investigated the involvement of the mechanosensitive ion channel Piezo and nitric oxide (NO) signaling.
- Validated findings in mammalian neurons in vitro and in vivo using pharmacological inhibition.
Main Results:
- Disrupting the ATR-Chek1 pathway (e.g., by removing Atr or Chek1, or overexpressing Cdc25) promoted regeneration in Drosophila sensory neurons.
- Overexpression of Atr or Chek1, or knockdown of Cdc25, impeded regeneration.
- Inhibition of the ATR-associated checkpoint complex enhanced regeneration and improved synapse/behavioral recovery after CNS injury.
- ATR activation was linked to mechanical stimuli during regeneration, mediated by Piezo and NO signaling, independent of DNA damage.
- Sensory neuron-specific knockout of Atr in mice and pharmacological inhibition of ATR-Chek1 in mammalian neurons and flies enhanced regeneration.
Conclusions:
- The Piezo-ATR-Chek1-Cdc25 axis acts as an evolutionarily conserved inhibitory mechanism for neuronal regeneration.
- Targeting this pathway presents a promising therapeutic strategy for promoting recovery from nervous system trauma.
