DCC Is Required for the Development of Nociceptive Topognosis in Mice and Humans
Ronan V. da Silva,
Helge C. Johannssen,
Matthias T. Wyss,
R. Brian Roome,
Farin B. Bourojeni,
Nicolas Stifani,
Ashley P.L. Marsh,
Monique M. Ryan,
Paul J. Lockhart,
Richard J. Leventer,
Linda J. Richards,
Bernard Rosenblatt,
Myriam Srour,
Bruno Weber,
Hanns Ulrich Zeilhofer,
Artur Kania
Affiliations
Ronan V. da Silva
Neural Circuit Development Laboratory, Institut de Recherches Cliniques de Montréal (IRCM), Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
Helge C. Johannssen
Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland
Matthias T. Wyss
Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland
R. Brian Roome
Neural Circuit Development Laboratory, Institut de Recherches Cliniques de Montréal (IRCM), Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
Farin B. Bourojeni
Neural Circuit Development Laboratory, Institut de Recherches Cliniques de Montréal (IRCM), Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
Nicolas Stifani
Neural Circuit Development Laboratory, Institut de Recherches Cliniques de Montréal (IRCM), Montreal, QC, Canada
Ashley P.L. Marsh
Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
Monique M. Ryan
Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; Department of Neurology, University of Melbourne, Royal Children’s Hospital, Parkville, VIC, Australia; Neuroscience Research Group, Murdoch Children’s Research Institute, Parkville, VIC, Australia
Paul J. Lockhart
Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
Richard J. Leventer
Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; Department of Neurology, University of Melbourne, Royal Children’s Hospital, Parkville, VIC, Australia; Neuroscience Research Group, Murdoch Children’s Research Institute, Parkville, VIC, Australia
Linda J. Richards
The University of Queensland, Queensland Brain Institute and School of Biomedical Sciences, St. Lucia, Brisbane, QLD, Australia
Bernard Rosenblatt
Division of Pediatric Neurology, Montreal Children’s Hospital, McGill University Health Centre (MUHC), and Departments of Pediatrics, Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
Myriam Srour
Division of Pediatric Neurology, Montreal Children’s Hospital, McGill University Health Centre (MUHC), and Departments of Pediatrics, Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
Bruno Weber
Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland
Hanns Ulrich Zeilhofer
Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland
Artur Kania
Neural Circuit Development Laboratory, Institut de Recherches Cliniques de Montréal (IRCM), Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada; Department of Anatomy and Cell Biology, Division of Experimental Medicine, McGill University, Montreal, QC, Canada; Corresponding author
Summary: Avoidance of environmental dangers depends on nociceptive topognosis, or the ability to localize painful stimuli. This is proposed to rely on somatotopic maps arising from topographically organized point-to-point connections between the body surface and the CNS. To determine the role of topographic organization of spinal ascending projections in nociceptive topognosis, we generated a conditional knockout mouse lacking expression of the netrin1 receptor DCC in the spinal cord. These mice have an increased number of ipsilateral spinothalamic connections and exhibit aberrant activation of the somatosensory cortex in response to unilateral stimulation. Furthermore, spinal cord-specific Dcc knockout animals displayed mislocalized licking responses to formalin injection, indicating impaired topognosis. Similarly, humans with DCC mutations experience bilateral sensation evoked by unilateral somatosensory stimulation. Collectively, our results constitute functional evidence of the importance of topographic organization of spinofugal connections for nociceptive topognosis. : Da Silva et al. show that the axon guidance receptor DCC is necessary for the lateralization of spinothalamic projections. Mice lacking Dcc in the spinal cord have abnormal somatosensory cortex activation in response to noxious stimulation and fail to accurately localize noxious stimuli. DCC mutations in humans lead to mirroring of somatosensory stimuli. Keywords: topographic organization, nociception, spinothalamic, DCC, commissural, behavior, mutation, mirror movement disorder, pain, somatosensory system, human genetics
