DCC Is Required for the Development of Nociceptive Topognosis in Mice and Humans

Abstract

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.