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Phosphatidylinositol transfer protein-α in netrin-1-induced PLC signalling and neurite outgrowth

Nature Cell Biology volume 7, pages 1124–1132 (2005)Cite this article

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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Figure 1: PITPα interaction with DCC and neogenin.
Figure 2: Netrin-1 stimulation of PI transfer activity of PITPα in a DCC-P3-domain-dependent manner.
Figure 3: PI(5)P regulation of PITPα activity that is required for netrin-1-induced PIP2 hydrolysis.
Figure 4: Requirement of PITPα for netrin-1-induced cortical neurite elongation.
Figure 5: Effects of PITPα in axon outgrowth in chicken and zebrafish embryos.

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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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Authors and Affiliations

  1. Institute of Molecular Medicine & Genomics and Department of Neurology, Medical College of Georgia, Augusta, 30912, GA, USA

    Zhu Feng, Cai-Xia Xi, Xiao-Juan Zhu & Wen-Cheng Xiong

  2. Institute of Molecular Medicine & Genomics and Department of Cell Biology and Anatomy, Medical College of Georgia, Augusta, 30912, GA, USA

    Sammy Navarre & David Kozlowski

  3. Department of Pathology, University of Alabama at Birmingham, Birmingham, 35294, AL, USA

    Yi Xie, Yan Hong, Lin Mei & Wen-Cheng Xiong

  4. Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Yu-Qiang Ding & Chun-Lei Wang

  5. Howard Hughes Medical Institute and the Jackson Laboratory, Bar Harbor, 04609, ME, USA

    S. L. Ackerman

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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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