title: Draxin inhibits axonal outgrowth through the netrin receptor DCC.
abstract: Draxin, a recently identified axon guidance protein, is essential for the formation of forebrain commissures, and can mediate repulsion of netrin-stimulated spinal commissural axons. Here, we report that draxin binds multiple netrin receptors: DCC (deleted in colorectal cancer), Neogenin, UNC5s (H1, H2, H3), and DSCAM (Down's syndrome cell adhesion molecule). Since draxin and Dcc knockouts showed similar phenotype in forebrain commissures formation, we show here the functional importance of draxin/DCC interaction. Draxin interacts with subnanomolar affinity to the netrin receptor DCC, in a region of DCC distinct from its netrin-binding domain. In vitro, neurite outgrowth from cortical and olfactory bulb explants of Dcc knock-out mice is significantly less inhibited by draxin, when compared with neurites from explants of wild-type mice. Furthermore, in comparison with wild-type mice, the growth cone collapse in response to draxin is largely abolished in Dcc-deficient cortical neurons. In vivo, double heteros of draxin/Dcc mice show markedly higher frequency of complete agenesis of corpus callosum than either of the single hetero. These results identify DCC as a convergent receptor for netrin and draxin in axon growth and guidance.
authors.affiliation: Division of Developmental Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Giasuddin
authors.initials: G
authors.lastname: Ahmed
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shinmyo
authors.forename: Kunimasa
authors.initials: K
authors.lastname: Ohta
authors.forename: Shahidul M
authors.initials: SM
authors.lastname: Islam
authors.forename: Mahmud
authors.initials: M
authors.lastname: Hossain
authors.forename: Iftekhar Bin
authors.initials: IB
authors.lastname: Naser
authors.forename: M Asrafuzzaman
authors.initials: MA
authors.lastname: Riyadh
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Su
authors.forename: Sanbing
authors.initials: S
authors.lastname: Zhang
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D002645:Chickens; D000075389:DCC Receptor; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D000075386:Netrin Receptors; D009433:Neural Inhibition / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D051381:Rats; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D000075389:DCC Receptor; C501909:DCC protein, human; C501910:Dcc protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C534831:draxin protein, mouse