Abstract
Neurite extension is essential for wiring the nervous system during development. Although several factors are known to regulate neurite outgrowth, the underlying mechanisms remain unclear. Here, we provide evidence for a role of phosphatidylinositol transfer protein-α (PITPα) in neurite extension in response to netrin-1, an extracellular guidance cue. PITPα interacts with the netrin receptor DCC (deleted in colorectal cancer) and neogenin. Netrin-1 stimulates PITPα binding to DCC and to phosphatidylinositol (5) phosphate [PI(5)P], increases its lipid-transfer activity and elevates hydrolysis of phosphatidylinositol bisphosphate (PIP2). In addition, the stimulated PIP2 hydrolysis requires PITPα. Furthermore, cortical explants of PITPα mutant mice are defective in extending neurites in response to netrin-1. Commissural neurons from chicken embryos expressing a dominant-negative PITPα mutant show reduced axon outgrowth. Morpholino-mediated knockdown of PITPα expression in zebrafish embryos leads to dose-dependent defects in motor-neuron axons and reduced numbers of spinal-cord neurons. Taken together, these results identify a crucial role for PITPα in netrin-1-induced neurite outgrowth, revealing a signalling mechanism for DCC/neogenin and PITPα regulation.
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Acknowledgements
We are grateful to Drs B.A. Hamilton (University of California at San Diego), B. Vogelstein (Johns Hopkins Medical School), M. Tessier-Lavigne, (Stanford University), J.Y. Wu and Y. Rao (Washington University) for reagents. We thank Dr R.-B. Markowitz (Medical College of Georgia) for reading the manuscript. This study was supported by grants from the National Institutes of Health (NS35900 for S.L.A.; DC006140 for D.K.; NS40480, NS045710 and NS44521 for L.M.; GM63861 and AR48120 for W.-C.X.; and the Philip Morris Research Program and Muscular Dystrophy Association for L.M.).
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Xie, Y., Ding, YQ., Hong, Y. et al. Phosphatidylinositol transfer protein-α in netrin-1-induced PLC signalling and neurite outgrowth. Nat Cell Biol 7, 1124–1132 (2005). https://doi.org/10.1038/ncb1321
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DOI: https://doi.org/10.1038/ncb1321
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