Amyloid precursor protein regulates netrin-1-mediated commissural axon outgrowth

J Biol Chem. 2012 Aug 24;287(35):30014-23. doi: 10.1074/jbc.M111.324780. Epub 2012 Jul 10.

Abstract

The multifunctional protein netrin-1 was initially discovered as the main attractive cue for commissural axon guidance by acting through its receptor DCC. Recently, we have shown that netrin-1 also interacts with the orphan transmembrane receptor amyloid precursor protein (APP). APP is cleaved by proteases, generating amyloid-β peptide, the main component of the amyloid plaques that are associated with Alzheimer disease. Our previous work demonstrated that via its interaction with APP, netrin-1 is a negative regulator of amyloid-β production in adult brain, but the biological relevance of APP/netrin-1 interaction under non-pathological conditions was unknown. We show here that during commissural axon navigation, APP, expressed at the growth cone, is part of the DCC receptor complex mediating netrin-1-dependent axon guidance. APP interacts with DCC in the presence of netrin-1 and enhances netrin-1-mediated DCC intracellular signaling, such as MAPK activation. Inactivation of APP in mice is associated with reduced commissural axon outgrowth. Thus, APP functionally acts as a co-receptor for DCC to mediate axon guidance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • DCC Receptor
  • Growth Cones / metabolism*
  • Growth Cones / pathology
  • Mice
  • Mice, Mutant Strains
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism*
  • Netrin-1
  • Proteolysis*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Amyloid beta-Protein Precursor
  • DCC Receptor
  • Dcc protein, mouse
  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • Netrin-1