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Neuron. 2019 Feb 15. pii: S0896-6273(19)30077-7. doi: 10.1016/j.neuron.2019.01.050. [Epub ahead of print]

The Mechanosensitive Ion Channel Piezo Inhibits Axon Regeneration.

Author information

1
Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: songy2@email.chop.edu.
2
Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
The Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Departments of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
6
Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
7
Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
8
Department of Neuroscience, The Scripps Research Institute, Howard Hughes Medical Institute, La Jolla, CA 92037, USA.
9
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
10
Departments of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
11
Departments of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: yuhnung.jan@ucsf.edu.

Abstract

Neurons exhibit a limited ability of repair. Given that mechanical forces affect neuronal outgrowth, it is important to investigate whether mechanosensitive ion channels may regulate axon regeneration. Here, we show that DmPiezo, a Ca2+-permeable non-selective cation channel, functions as an intrinsic inhibitor for axon regeneration in Drosophila. DmPiezo activation during axon regeneration induces local Ca2+ transients at the growth cone, leading to activation of nitric oxide synthase and the downstream cGMP kinase Foraging or PKG to restrict axon regrowth. Loss of DmPiezo enhances axon regeneration of sensory neurons in the peripheral and CNS. Conditional knockout of its mammalian homolog Piezo1 in vivo accelerates regeneration, while its pharmacological activation in vitro modestly reduces regeneration, suggesting the role of Piezo in inhibiting regeneration may be evolutionarily conserved. These findings provide a precedent for the involvement of mechanosensitive channels in axon regeneration and add a potential target for modulating nervous system repair.

KEYWORDS:

Drosophila; Piezo; axon regeneration; corneal sensory nerve; dendritic arborization neurons; ion channels; mammalian injury model; mechanosensitive; nitric oxide synthase

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