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.
Bibliographical noteFunding 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.
© 2023 The Author(s)
- axonal degeneration
- CP: Neuroscience