Kinesin family member 2A gates nociception

Swagata Dey; Omer Barkai; Irena Gokhman; Sapir Suissa; Rebecca Haffner-Krausz; Noa Wigoda; Ester Feldmesser; Shifra Ben-Dor; Andrew Kovalenko; Alexander Binshtok; Avraham Yaron

doi:10.1016/j.celrep.2023.113257

Kinesin family member 2A gates nociception

Swagata Dey, Omer Barkai, Irena Gokhman, Sapir Suissa, Rebecca Haffner-Krausz, Noa Wigoda, Ester Feldmesser, Shifra Ben-Dor, Andrew Kovalenko, Alexander Binshtok, Avraham Yaron^*

^*Corresponding author for this work

Department of Medical Neurobiology

Research output: Contribution to journal › Article › peer-review

Abstract

Nociceptive axons undergo remodeling as they innervate their targets during development and in response to environmental insults and pathological conditions. How is nociceptive morphogenesis regulated? Here, we show that the microtubule destabilizer kinesin family member 2A (Kif2a) is a key regulator of nociceptive terminal structures and pain sensitivity. Ablation of Kif2a in sensory neurons causes hyperinnervation and hypersensitivity to noxious stimuli in young adult mice, whereas touch sensitivity and proprioception remain unaffected. Computational modeling predicts that structural remodeling is sufficient to explain the phenotypes. Furthermore, Kif2a deficiency triggers a transcriptional response comprising sustained upregulation of injury-related genes and homeostatic downregulation of highly specific channels and receptors at the late stage. The latter effect can be predicted to relieve the hyperexcitability of nociceptive neurons, despite persisting morphological aberrations, and indeed correlates with the resolution of pain hypersensitivity. Overall, we reveal a critical control node defining nociceptive terminal structure, which is regulating nociception.

Original language	American English
Article number	113257
Journal	Cell Reports
Volume	42
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2023.113257
State	Published - 31 Oct 2023

Bibliographical note

Funding Information:
We thank the A.Y. lab members for advice and criticism, Letizia Marvaldi and Michael Tsoory for their help with the behavioral assays, Vladimir Kiss for help with the confocal microscopy, Rotem Ben Tov Perry for help with the RNA preparations, Ron Rotkopf for excellent statistical assistance, Ofer Yizhar for help with the optogenetic system, and Michael Fainzilber for critically reading the manuscript. This work was supported by funding to A.Y. by Israel Science Foundation grants 2495/21 and 3243/20 ; The Minerva Foundation ; The David and Fela Shapell Family Center for Genetic Disorders Research ; The Kekst Family Institute for Medical Genetics ; The Belle S. and Irving E. Meller Center for the Biology of Aging ; The Nella and Leon Benoziyo Center for Neurological Diseases ; and The Weizmann Center for Research on Neurodegeneration at The Weizmann Institute of Science. Support to A.B. from the Israel Science Foundation , grant agreements 1202/23 and 1470/17 , and the Deutsch-Israelische Projectkooperation program of Deutsche Forschungsgemeinschaft (DIP) grant agreement B.I. 1665/1-1ZI1172/12-1 and Sessile and Seymour Alpert Chair in Pain Research is gratefully acknowledged. A.Y. is an incumbent of the Jack & Simon Djanogly Professorial Chair in Biochemistry.

Publisher Copyright:
© 2023 The Author(s)

Keywords

axonal degeneration
CP: Neuroscience
Kif2a
microtubules
nociception

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10.1016/j.celrep.2023.113257

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title = "Kinesin family member 2A gates nociception",

abstract = "Nociceptive axons undergo remodeling as they innervate their targets during development and in response to environmental insults and pathological conditions. How is nociceptive morphogenesis regulated? Here, we show that the microtubule destabilizer kinesin family member 2A (Kif2a) is a key regulator of nociceptive terminal structures and pain sensitivity. Ablation of Kif2a in sensory neurons causes hyperinnervation and hypersensitivity to noxious stimuli in young adult mice, whereas touch sensitivity and proprioception remain unaffected. Computational modeling predicts that structural remodeling is sufficient to explain the phenotypes. Furthermore, Kif2a deficiency triggers a transcriptional response comprising sustained upregulation of injury-related genes and homeostatic downregulation of highly specific channels and receptors at the late stage. The latter effect can be predicted to relieve the hyperexcitability of nociceptive neurons, despite persisting morphological aberrations, and indeed correlates with the resolution of pain hypersensitivity. Overall, we reveal a critical control node defining nociceptive terminal structure, which is regulating nociception.",

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author = "Swagata Dey and Omer Barkai and Irena Gokhman and Sapir Suissa and Rebecca Haffner-Krausz and Noa Wigoda and Ester Feldmesser and Shifra Ben-Dor and Andrew Kovalenko and Alexander Binshtok and Avraham Yaron",

note = "Funding Information: We thank the A.Y. lab members for advice and criticism, Letizia Marvaldi and Michael Tsoory for their help with the behavioral assays, Vladimir Kiss for help with the confocal microscopy, Rotem Ben Tov Perry for help with the RNA preparations, Ron Rotkopf for excellent statistical assistance, Ofer Yizhar for help with the optogenetic system, and Michael Fainzilber for critically reading the manuscript. This work was supported by funding to A.Y. by Israel Science Foundation grants 2495/21 and 3243/20 ; The Minerva Foundation ; The David and Fela Shapell Family Center for Genetic Disorders Research ; The Kekst Family Institute for Medical Genetics ; The Belle S. and Irving E. Meller Center for the Biology of Aging ; The Nella and Leon Benoziyo Center for Neurological Diseases ; and The Weizmann Center for Research on Neurodegeneration at The Weizmann Institute of Science. Support to A.B. from the Israel Science Foundation , grant agreements 1202/23 and 1470/17 , and the Deutsch-Israelische Projectkooperation program of Deutsche Forschungsgemeinschaft (DIP) grant agreement B.I. 1665/1-1ZI1172/12-1 and Sessile and Seymour Alpert Chair in Pain Research is gratefully acknowledged. A.Y. is an incumbent of the Jack & Simon Djanogly Professorial Chair in Biochemistry. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

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AU - Barkai, Omer

AU - Gokhman, Irena

AU - Suissa, Sapir

AU - Haffner-Krausz, Rebecca

AU - Wigoda, Noa

AU - Feldmesser, Ester

AU - Ben-Dor, Shifra

AU - Kovalenko, Andrew

AU - Binshtok, Alexander

AU - Yaron, Avraham

N1 - Funding Information: We thank the A.Y. lab members for advice and criticism, Letizia Marvaldi and Michael Tsoory for their help with the behavioral assays, Vladimir Kiss for help with the confocal microscopy, Rotem Ben Tov Perry for help with the RNA preparations, Ron Rotkopf for excellent statistical assistance, Ofer Yizhar for help with the optogenetic system, and Michael Fainzilber for critically reading the manuscript. This work was supported by funding to A.Y. by Israel Science Foundation grants 2495/21 and 3243/20 ; The Minerva Foundation ; The David and Fela Shapell Family Center for Genetic Disorders Research ; The Kekst Family Institute for Medical Genetics ; The Belle S. and Irving E. Meller Center for the Biology of Aging ; The Nella and Leon Benoziyo Center for Neurological Diseases ; and The Weizmann Center for Research on Neurodegeneration at The Weizmann Institute of Science. Support to A.B. from the Israel Science Foundation , grant agreements 1202/23 and 1470/17 , and the Deutsch-Israelische Projectkooperation program of Deutsche Forschungsgemeinschaft (DIP) grant agreement B.I. 1665/1-1ZI1172/12-1 and Sessile and Seymour Alpert Chair in Pain Research is gratefully acknowledged. A.Y. is an incumbent of the Jack & Simon Djanogly Professorial Chair in Biochemistry. Publisher Copyright: © 2023 The Author(s)

PY - 2023/10/31

Y1 - 2023/10/31

N2 - Nociceptive axons undergo remodeling as they innervate their targets during development and in response to environmental insults and pathological conditions. How is nociceptive morphogenesis regulated? Here, we show that the microtubule destabilizer kinesin family member 2A (Kif2a) is a key regulator of nociceptive terminal structures and pain sensitivity. Ablation of Kif2a in sensory neurons causes hyperinnervation and hypersensitivity to noxious stimuli in young adult mice, whereas touch sensitivity and proprioception remain unaffected. Computational modeling predicts that structural remodeling is sufficient to explain the phenotypes. Furthermore, Kif2a deficiency triggers a transcriptional response comprising sustained upregulation of injury-related genes and homeostatic downregulation of highly specific channels and receptors at the late stage. The latter effect can be predicted to relieve the hyperexcitability of nociceptive neurons, despite persisting morphological aberrations, and indeed correlates with the resolution of pain hypersensitivity. Overall, we reveal a critical control node defining nociceptive terminal structure, which is regulating nociception.

AB - Nociceptive axons undergo remodeling as they innervate their targets during development and in response to environmental insults and pathological conditions. How is nociceptive morphogenesis regulated? Here, we show that the microtubule destabilizer kinesin family member 2A (Kif2a) is a key regulator of nociceptive terminal structures and pain sensitivity. Ablation of Kif2a in sensory neurons causes hyperinnervation and hypersensitivity to noxious stimuli in young adult mice, whereas touch sensitivity and proprioception remain unaffected. Computational modeling predicts that structural remodeling is sufficient to explain the phenotypes. Furthermore, Kif2a deficiency triggers a transcriptional response comprising sustained upregulation of injury-related genes and homeostatic downregulation of highly specific channels and receptors at the late stage. The latter effect can be predicted to relieve the hyperexcitability of nociceptive neurons, despite persisting morphological aberrations, and indeed correlates with the resolution of pain hypersensitivity. Overall, we reveal a critical control node defining nociceptive terminal structure, which is regulating nociception.

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KW - CP: Neuroscience

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KW - microtubules

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DO - 10.1016/j.celrep.2023.113257

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C2 - 37851573

AN - SCOPUS:85174148618

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 10

M1 - 113257

ER -

Kinesin family member 2A gates nociception

Abstract

Bibliographical note

Keywords

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