Nogo receptor homolog NgR2 expressed in sensory DRG neurons controls epidermal innervation by interaction with Versican.
Primary sensory afferents of the dorsal root ganglion (DRG) that innervate the skin detect a wide range of stimuli, such as touch, temperature, pain, and itch. Different functional classes of nociceptors project their axons to distinct target zones within the developing skin, but the molecular mechanisms that regulate target innervation are less clear. Here we report that the Nogo66 receptor homolog NgR2 is essential for proper cutaneous innervation. NgR2(-/-) mice display increased density of nonpeptidergic nociceptors in the footpad and exhibit enhanced sensitivity to mechanical force and innocuous cold temperatures. These sensory deficits are not associated with any abnormality in morphology or density of DRG neurons. However, deletion of NgR2 renders nociceptive nonpeptidergic sensory neurons insensitive to the outgrowth repulsive activity of skin-derived Versican. Biochemical evidence shows that NgR2 specifically interacts with the G3 domain of Versican. The data suggest that Versican/NgR2 signaling at the dermo-epidermal junction acts in vivo as a local suppressor of axonal plasticity to control proper density of epidermal sensory fiber innervation. Our findings not only reveal the existence of a novel and unsuspected mechanism regulating epidermal target innervation, but also provide the first evidence for a physiological role of NgR2 in the peripheral nervous system.
Division of Neurobiochemistry, Biocenter, Innsbruck Medical University, 6020 Innsbruck, Austria and Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
Bastian E
BE
Bäumer
Antje
A
Kurz
Sarah C
SC
Borrie
Stephan
S
Sickinger
María T
MT
Dours-Zimmermann
Dieter R
DR
Zimmermann
Christine E
CE
Bandtlow
D000818:Animals; D000831:Animals, Newborn; D016466:CHO Cells; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D003412:Cricetulus; D004817:Epidermis / Q000294:innervation*; D044783:F-Box Proteins; D005727:Ganglia, Spinal / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006023:Glycoproteins / Q000378:metabolism; D006930:Hyperalgesia / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D016900:Neurofilament Proteins / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism; D000070817:Nogo Receptor 2; D017288:Pain Threshold / Q000502:physiology; D010812:Physical Stimulation / Q000009:adverse effects; D011485:Protein Binding / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D058469:Receptors, Purinergic P2X / Q000235:genetics / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000145:classification / Q000166:cytology / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D053675:Versicans / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D044783:F-Box Proteins; D006023:Glycoproteins; D016900:Neurofilament Proteins; D000070817:Nogo Receptor 2; D011956:Receptors, Cell Surface; D058469:Receptors, Purinergic P2X; C571038:Rtn4rl2 protein, mouse; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014404:Tubulin; C462941:beta3 tubulin, mouse; C473590:isolectin B4-binding glycoprotein, mouse; C051774:neurofilament protein H; D053675:Versicans; D015740:Calcitonin Gene-Related Peptide