Phosphatidylinositol-3-Kinase–Atypical Protein Kinase C Signaling Is Required for Wnt Attraction and Anterior–Posterior Axon Guidance
| Autor: | Ali G. Fenstermaker, Yimin Zou, Alex M. Wolf, Charles Lo, Anna I Lyuksyutova, Beth Shafer |
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| Rok vydání: | 2008 |
| Předmět: |
Frizzled
Protein subunit Green Fluorescent Proteins Biology Transfection Wortmannin Mice Phosphatidylinositol 3-Kinases chemistry.chemical_compound Organ Culture Techniques Wnt4 Protein Heterotrimeric G protein Chlorocebus aethiops Animals Enzyme Inhibitors Growth cone Protein Kinase C Neurons Kinase General Neuroscience Wnt signaling pathway Gene Expression Regulation Developmental Articles Embryo Mammalian Axons Wnt Proteins Electroporation Spinal Cord chemistry COS Cells Mutation Axon guidance Neuroscience Signal Transduction |
| Zdroj: | The Journal of Neuroscience. 28:3456-3467 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | 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 PKCzeta pseudosubstrate, a specific blocker of aPKC activity, and expression of a kinase-defective PKCzeta mutant in commissural neurons resulted in A-P randomization in "open-book" explants. Upstream of PKCzeta, heterotrimeric G-proteins and phosphatidylinositol-3-kinases (PI3Ks), are also required for A-P guidance, because pertussis toxin, wortmannin, and expression of a p110gamma kinase-defective construct all resulted in A-P randomization. Overexpression of p110gamma, the catalytic subunit of PI3Kgamma, 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. |
| Databáze: | OpenAIRE |
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