Phosphatidylinositol Transfer Protein-Alpha in netrin-1-induced PLC Signalling and Neurite Outgrowth

Nat Cell Biol. 2005 Nov;7(11):1124-32. doi: 10.1038/ncb1321.

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-alpha (PlTPalpha) in neurite extension in response to netrin-1, an extracellular guidance cue. PlTPalpha interacts with the netrin receptor DCC (deleted in colorectal cancer) and neogenin. Netrin-1 stimulates PlTPalpha binding to DCC and to phosphatidylinositol (5) phosphate [Pl(5)P], increases its lipid-transfer activity and elevates hydrolysis of phosphatidylinositol bisphosphate (PlP2). In addition, the stimulated PIP2 hydrolysis requires PlTPalpha. Furthermore, cortical explants of PlTPalpha mutant mice are defective in extending neurites in response to netrin-1. Commissural neurons from chicken embryos expressing a dominant-negative PlTPalpha mutant show reduced axon outgrowth. Morpholino-mediated knockdown of PlTPalpha 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 PlTPalpha in netrin-1-induced neurite outgrowth, revealing a signalling mechanism for DCC/neogenin and PlTPalpha regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chick Embryo / cytology*
  • Chick Embryo / metabolism
  • DCC Receptor
  • Humans
  • Lipid Metabolism / physiology
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology
  • Nerve Growth Factors / physiology*
  • Netrin-1
  • Neurites / metabolism*
  • Neurons / cytology
  • Neurons / metabolism
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Phospholipid Transfer Proteins / metabolism
  • Phospholipid Transfer Proteins / physiology*
  • Receptors, Cell Surface / metabolism
  • Signal Transduction / drug effects
  • Transfection
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / physiology*
  • Zebrafish / embryology
  • Zebrafish / physiology
  • Zebrafish Proteins

Substances

  • DCC Receptor
  • DCC protein, human
  • Membrane Proteins
  • NTN1 protein, human
  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Phosphatidylinositol 4,5-Diphosphate
  • Phospholipid Transfer Proteins
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • Zebrafish Proteins
  • neogenin
  • neurite-inducing factor
  • Netrin-1