title: TACE cleaves neogenin to desensitize cortical neurons to the repulsive guidance molecule.
abstract: Neogenin is a receptor for netrins and proteins of the repulsive guidance molecule (RGM) family. It regulates several key developmental processes within the nervous system. The binding of RGMa to neogenin induces the inhibition of neurite outgrowth and the collapse of the growth cone of neurons. Here, we report that a disintegrin and metalloprotease (ADAM) transmembrane protein regulates the sensitivity of neurons to RGMa, by inducing the shedding of the ectodomain of neogenin. The extracellular domain of neogenin is directly associated with and cleaved off by the tumor necrosis factor-α converting enzyme (TACE), also called ADAM17. TACE is endogenously expressed in embryonic cortical neurons and regulates the cleavage of neogenin, and the inhibition of TACE in turn enhances RGMa-induced inhibition of neurite outgrowth and collapse of the growth cone. Conversely, exogenous expression of TACE abolishes the effect of RGMa. Therefore, TACE may play a role in modulating the RGM-induced repulsive behavior of neurons by regulating the expression of neogenin on the cell surface.
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okamura
authors.forename: Eiji
authors.initials: E
authors.lastname: Kohmura
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yamashita
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000072198:ADAM17 Protein; D000818:Animals; D016466:CHO Cells; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000196:embryology; D006224:Cricetinae; D003412:Cricetulus; D058851:GPI-Linked Proteins; D057809:HEK293 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000633:toxicity*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C502259:RGM protein, rat; C091279:neogenin; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat