DSCAM functions as a netrin receptor in commissural axon pathfinding.
Down syndrome cell adhesion molecule (DSCAM) is required for axon guidance and dendrite arborization. How DSCAM functions in vertebrates is not well understood. Here we show that DSCAM is expressed on commissural axons and interacts with Netrin-1, a prototypical guidance cue for commissural axons. The knockdown of DSCAM by specific siRNA or blockage of DSCAM signaling by overexpression of a mutant lacking its intracellular domain inhibits netrin-induced axon outgrowth and commissural axon turning in vitro. SiRNA-mediated knockdown of DSCAM in ovo causes defects in commissural axon projection and pathfinding. In transfected cells, DSCAM by itself, in the absence of DCC, is capable of mediating netrin signaling in activating phosphorylation of Fyn and Pak1. These findings demonstrate an essential role of vertebrate DSCAM in axon guidance, indicating that DSCAM functions as a receptor of netrin-1. Our data suggest previously unexpected complexity in receptors that mediate vertebrate netrin signaling.
Liu
Guofa
G
Department of Neurology and Robert H. Lurie Comprehensive Cancer Center, Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Li
Weiquan
W
Wang
Lei
L
Kar
Amar
A
Guan
Kun-Liang
KL
Rao
Yi
Y
Wu
Jane Y
JY
D000818:Animals; D001369:Axons; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002642:Chick Embryo; D055785:Gene Knockdown Techniques; D006801:Humans; D047468:Immunoprecipitation; D009414:Nerve Growth Factors / Q000378:metabolism; D000075386:Netrin Receptors; D000075388:Netrin-1; D010766:Phosphorylation; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D015815:Cell Adhesion Molecules; C110833:DSCAM protein, human; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1