Liu Guofa, Li Weiquan, Wang Lei, Kar Amar, Guan Kun-Liang, Rao Yi, Wu Jane Y
Department of Neurology and Robert H. Lurie Comprehensive Cancer Center, Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2951-6. doi: 10.1073/pnas.0811083106. Epub 2009 Feb 5.
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.
唐氏综合征细胞粘附分子（DSCAM）是轴突导向和树突分支所必需的。DSCAM在脊椎动物中如何发挥作用尚不清楚。在这里，我们表明DSCAM在连合轴突上表达，并与Netrin-1相互作用，Netrin-1是连合轴突的典型导向信号。通过特异性siRNA敲低DSCAM或通过过表达缺乏其细胞内结构域的突变体来阻断DSCAM信号传导，可抑制netrin诱导的体外轴突生长和连合轴突转向。卵内siRNA介导的DSCAM敲低会导致连合轴突投射和路径寻找缺陷。在转染细胞中，DSCAM自身在没有DCC的情况下，能够介导netrin信号传导，激活Fyn和Pak1的磷酸化。这些发现证明了脊椎动物DSCAM在轴突导向中的重要作用，表明DSCAM作为netrin-1的受体发挥作用。我们的数据表明，介导脊椎动物netrin信号传导的受体存在先前未预料到的复杂性。
