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The Journal of Neuroscience, March 26, 2008, 28(13):3456-3467; doi:10.1523/JNEUROSCI.0029-08.2008

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Development/Plasticity/Repair
Phosphatidylinositol-3-Kinase–Atypical Protein Kinase C Signaling Is Required for Wnt Attraction and Anterior–Posterior Axon Guidance

Alex M. Wolf,^2 * Anna I. Lyuksyutova,^2 * Ali G. Fenstermaker,^3,4 Beth Shafer,³ Charles G. Lo,³ and Yimin Zou^1,2,3,4

¹Department of Neurobiology, Pharmacology, and Physiology and ²Committee on Developmental Biology, The University of Chicago, Chicago, Illinois 60637, and ³Neurobiology Section, Biological Sciences Division, and ⁴Neuroscience Program, University of California, San Diego, La Jolla, California 92093

Correspondence should be addressed to Yimin Zou at the above address. Email: yzou{at}ucsd.edu

Wnt proteins are conserved axon guidance cues that control growth cone navigation. However, the intracellular signaling mechanisms that mediate growth cone turning in response to Wnts are unknown. We previously showed that Wnt–Frizzled signaling directs spinal cord commissural axons to turn anteriorly after midline crossing through an attractive mechanism. Here we show that atypical protein kinase C (aPKC), is required for Wnt-mediated attraction of commissural axons and proper anterior–posterior (A–P) pathfinding. A PKC pseudosubstrate, a specific blocker of aPKC activity, and expression of a kinase-defective PKC mutant in commissural neurons resulted in A–P randomization in "open-book" explants. Upstream of PKC, heterotrimeric G-proteins and phosphatidylinositol-3-kinases (PI3Ks), are also required for A–P guidance, because pertussis toxin, wortmannin, and expression of a p110 kinase-defective construct all resulted in A–P randomization. Overexpression of p110, the catalytic subunit of PI3K, caused precocious anterior turning of commissural axons before midline crossing in open-book explants and caused dissociated precrossing commissural axons, which are normally insensitive to Wnt attraction, to turn toward Wnt4-expressing cells. Therefore, we propose that atypical PKC signaling is required for Wnt-mediated A–P axon guidance and that PI3K can act as a switch to activate Wnt responsiveness during midline crossing.

Key words: midline; PKC; phosphoinositides; p110; p110; Frizzled

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Received Nov. 13, 2007; revised Feb. 7, 2008; accepted Feb. 11, 2008.

Correspondence should be addressed to Yimin Zou at the above address. Email: yzou{at}ucsd.edu

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