NGL-2 Is a New Partner of PAR Complex in Axon Differentiation

J Neurosci. 2015 May 6;35(18):7153-64. doi: 10.1523/JNEUROSCI.4726-14.2015.


Neuronal polarization is pivotal for neural network formation during brain development. Axon differentiation is a hallmark of initial neuronal polarization. Here, we report that the leucine-rich repeat-containing protein netrin-G ligand-2 (NGL-2) as a polarity regulator that localizes asymmetrically in rat hippocampal neurons and is required for differentiation of the future axon. NGL-2 was associated with PAR complex, and this interaction resulted in local stabilization of axonal microtubules. Further study showed that the C terminal of NGL-2 binds to the PDZ domain of PAR6, and NGL-2 interacts with PAR3 and atypical PKCζ (aPKCζ), with PAR6 acting as a bridge or modifier. Then, NGL-2 regulates the local stabilization of microtubules and promotes axon differentiation by the aPKCζ/microtubule affinity-regulating kinase 2 pathway. These findings reveal the critical role of NGL-2 in regulating axon differentiation in rat hippocampal neurons and reveal a novel partner of the PAR complex.

Keywords: LRRC4; NGL-2; axon differentiation; microtubule stability; neuronal polarity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Axons / metabolism*
  • Carrier Proteins / metabolism*
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Female
  • GPI-Linked Proteins / metabolism*
  • HEK293 Cells
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Male
  • Nerve Tissue Proteins / metabolism*
  • Netrins
  • Rats


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • GPI-Linked Proteins
  • NTNG2 protein, human
  • Nerve Tissue Proteins
  • Netrins
  • Pard3 protein, rat
  • Pard6a protein, rat