Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture

Cell. 2013 Jun 20;153(7):1510-25. doi: 10.1016/j.cell.2013.05.021.

Abstract

The molecular mechanisms underlying the axon arborization of mammalian neurons are poorly understood but are critical for the establishment of functional neural circuits. We identified a pathway defined by two kinases, LKB1 and NUAK1, required for cortical axon branching in vivo. Conditional deletion of LKB1 after axon specification or knockdown of NUAK1 drastically reduced axon branching in vivo, whereas their overexpression was sufficient to increase axon branching. The LKB1-NUAK1 pathway controls mitochondria immobilization in axons. Using manipulation of Syntaphilin, a protein necessary and sufficient to arrest mitochondrial transport specifically in the axon, we demonstrate that the LKB1-NUAK1 kinase pathway regulates axon branching by promoting mitochondria immobilization. Finally, we show that LKB1 and NUAK1 are necessary and sufficient to immobilize mitochondria specifically at nascent presynaptic sites. Our results unravel a link between presynaptic mitochondrial capture and axon branching.

Publication types

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

MeSH terms

  • Animals
  • Axons / metabolism*
  • Cell Movement
  • Cells, Cultured
  • Female
  • Gene Deletion
  • Gene Knockdown Techniques
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism*
  • Nerve Tissue Proteins
  • Neurons / cytology*
  • Neurons / metabolism
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Repressor Proteins / metabolism*
  • Signal Transduction*

Substances

  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Repressor Proteins
  • Snph protein, mouse
  • Protein Kinases
  • NUAK1 protein, mouse
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases