Department of Biomolecular Sciences and Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot 76100, Israel
Omer Barkai
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah School of Medicine, Jerusalem 91120, Israel; The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel; F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Irena Gokhman
Department of Biomolecular Sciences and Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot 76100, Israel
Sapir Suissa
Department of Biomolecular Sciences and Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot 76100, Israel
Rebecca Haffner-Krausz
Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel
Noa Wigoda
Bioinformatics Unit, Life Science Core Facilities, Weizmann Institute of Science, Rehovot 76100, Israel
Ester Feldmesser
Bioinformatics Unit, Life Science Core Facilities, Weizmann Institute of Science, Rehovot 76100, Israel
Shifra Ben-Dor
Bioinformatics Unit, Life Science Core Facilities, Weizmann Institute of Science, Rehovot 76100, Israel
Andrew Kovalenko
Department of Biomolecular Sciences and Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot 76100, Israel
Alexander Binshtok
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah School of Medicine, Jerusalem 91120, Israel; The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
Avraham Yaron
Department of Biomolecular Sciences and Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot 76100, Israel; Corresponding author
Summary: 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.
