Journal Article

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

Noristani, Harun N., Li, Dan, Trombley, Shannon, Li, Shuxin, Goldshteyn, Jessica I., Niu, Jingwen, Brewster, Megan, Li, Feng, Lo, Tsz Y., Song, Yuanquan, Pogoda, Katarzyna, Wang, Chuxi, Wang, Shuchao, Rompolas, Panteleimon, Mandal, Kalpana, Thomas, Gareth M., Miles, Leann, Qiu, Jingyun, He, Ye, Janmey, Paul A., Wang, Qin

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 13/62 / 14 / 14/19 / 14/69 / 38 / 42 / 631/378/1687 / 631/378/340 / 631/378/87 / 631/80/304 / 64/24 / Animals / Animals, Genetically Modified / Ataxia Telangiectasia Mutated Proteins - genetics / Ataxia Telangiectasia Mutated Proteins - metabolism / Axons - metabolism / Cell cycle / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Central nervous system / Checkpoint Kinase 1 - genetics / Checkpoint Kinase 1 - metabolism / Damage / Deoxyribonucleic acid / DNA / DNA damage / Drosophila melanogaster - genetics / Drosophila melanogaster - metabolism / Drosophila Proteins - genetics / Drosophila Proteins - metabolism / HEK293 Cells / Humanities and Social Sciences / Humans / Ion channels / Ion Channels - genetics / Ion Channels - metabolism / Kinases / Mechanotransduction / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / multidisciplinary / Nerve Regeneration - genetics / Nervous system / Neurons / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Protein-serine/threonine kinase / Recovery / Recovery of function / Regeneration / Science / Science (multidisciplinary) / Sensory neurons / Signal Transduction - genetics / Single-stranded DNA / Synapses / Target recognition / Therapeutic targets / Trauma