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Merck

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

Nature communications (2021-06-24)
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, Yuanquan Song
RESUMEN

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.

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Sigma-Aldrich
ANTI-FLAG® M2 monoclonal antibody produced in mouse, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)
Sigma-Aldrich
Anti-CHEK1 antibody produced in rabbit, affinity isolated antibody