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

Yi Xie, Yu Qiang Ding, Yan Hong, Zhu Feng, Sammy Navarre, Cai Xia Xi, Xiao Juan Zhu, Chun Lei Wang, S. L. Ackerman, David Kozlowski, Lin Mei, Wen Cheng Xiong

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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.

Original languageEnglish (US)
Pages (from-to)1124-1132
Number of pages9
JournalNature Cell Biology
Volume7
Issue number11
DOIs
StatePublished - Nov 1 2005

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Xie, Y., Ding, Y. Q., Hong, Y., Feng, Z., Navarre, S., Xi, C. X., Zhu, X. J., Wang, C. L., Ackerman, S. L., Kozlowski, D., Mei, L., & Xiong, W. C. (2005). Phosphatidylinositol transfer protein-α in netrin-1-induced PLC signalling and neurite outgrowth. Nature Cell Biology, 7(11), 1124-1132. https://doi.org/10.1038/ncb1321