Draxin inhibits axonal outgrowth through the netrin receptor DCC

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,...

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Bibliographic Details
Published in:The Journal of neuroscience 2011-09, Vol.31 (39), p.14018-14023
Main Authors: Ahmed, Giasuddin, Shinmyo, Yohei, Ohta, Kunimasa, Islam, Shahidul M, Hossain, Mahmud, Naser, Iftekhar Bin, Riyadh, M Asrafuzzaman, Su, Yuhong, Zhang, Sanbing, Tessier-Lavigne, Marc, Tanaka, Hideaki
Format: Article
Language:English
Subjects:
Animals
Axons - physiology
Brief Communications
Chickens
DCC Receptor
HEK293 Cells
Humans
Intercellular Signaling Peptides and Proteins - genetics
Intercellular Signaling Peptides and Proteins - physiology
Mice
Mice, Knockout
Netrin Receptors
Neural Inhibition - genetics
Neural Inhibition - physiology
Protein Binding - genetics
Protein Binding - physiology
Protein Structure, Tertiary - genetics
Protein Structure, Tertiary - physiology
Rats
Receptors, Cell Surface - deficiency
Receptors, Cell Surface - genetics
Receptors, Cell Surface - physiology
Tumor Suppressor Proteins - deficiency
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - physiology
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Summary: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.
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.0943-11.2011