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The Journal of Neuroscience, January 24, 2007, 27(4):957-968; doi:10.1523/JNEUROSCI.4616-06.2007

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 Previous Article

Development/Plasticity/Repair
p130^CAS Is Required for Netrin Signaling and Commissural Axon Guidance

Guofa Liu,¹ Weiquan Li,³ Xue Gao,^1,2 Xiaoling Li,¹ Claudia Jürgensen,¹ Hwan-Tae Park,⁴ Nah-Young Shin,⁵ Jian Yu,¹ Ming-Liang He,⁶ Steven K. Hanks,⁵ Jane Y. Wu,^1,2 Kun-Liang Guan,³ and Yi Rao¹

¹Department of Neurology, ²Robert H. Lurie Comprehensive Cancer Center, Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, ³Life Sciences Institute, Department of Biological Chemistry, and Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 48109, ⁴Department of Physiology, College of Medicine, Dong-A University, Seo-Gu, Pusan 602-714, South Korea, ⁵Department of Cell and Developmental Biology, U-4206 Learned Laboratory, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and ⁶The Center for Emerging Infectious Diseases, School of Public Health, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong

Correspondence should be addressed to Yi Rao, Department of Neurology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Ward 10-185, Chicago, IL 60611. Email: y-rao{at}northwestern.edu

Netrins are an important family of axon guidance cues. Here, we report that netrin-1 induces tyrosine phosphorylation of p130^CAS (Crk-associated substrate). Our biochemical studies indicate that p130^CAS is downstream of the Src family kinases and upstream of the small GTPase Rac1 and Cdc42. Inhibition of p130^CAS signaling blocks both the neurite outgrowth-promoting activity and the axon attraction activity of netrin-1. p130^CAS RNA interference inhibits the attraction of commissural axons in the spinal cord by netrin-1 and causes defects in commissural axon projection in the embryo. These results demonstrate that p130^CAS is a key component in the netrin signal transduction pathway and plays an important role in guiding commissural axons in vivo.

Key words: netrin-1; p130^CAS; Rac1; Cdc42; signaling; commissural axons

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Received Oct. 24, 2006; revised Dec. 12, 2006; accepted Dec. 14, 2006.

Correspondence should be addressed to Yi Rao, Department of Neurology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Ward 10-185, Chicago, IL 60611. Email: y-rao{at}northwestern.edu

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