Kalirin Dbl-homology guanine nucleotide exchange factor 1 domain initiates new axon outgrowths via RhoG-mediated mechanisms

J Neurosci. 2002 Aug 15;22(16):6980-90. doi: 10.1523/JNEUROSCI.22-16-06980.2002.


The large multidomain Kalirin and Trio proteins containing dual Rho GTPase guanine nucleotide exchange factor (GEF) domains have been implicated in the regulation of neuronal fiber extension and pathfinding during development. In mammals, Kalirin is expressed predominantly in the nervous system, whereas Trio, broadly expressed throughout the body, is expressed at a lower level in the nervous system. To evaluate the role of Kalirin in fiber initiation and outgrowth, we microinjected cultured sympathetic neurons with vectors encoding Kalirin or with Kalirin antisense oligonucleotides, and we assessed neuronal fiber growth in a serum-free, satellite cell-free environment. Kalirin antisense oligonucleotides blocked the continued extension of preexisting axons. Kalirin overexpression induced the prolific sprouting of new axonal fibers that grew at the normal rate; the activity of Kalirin was entirely dependent on the activity of the first GEF domain. KalGEF1-induced sprouting of new fibers from lamellipodial structures was accompanied by extensive actin cytoskeleton reorganization. The kalGEF1 phenotype was mimicked by constitutively active RhoG and was blocked by RhoG inhibitors. Constitutively active Rac1, RhoA, and Cdc42 were unable to initiate new axons, whereas dominant-negative Rac1, RhoA, and Cdc42 failed to block axon sprouting. Thus Kalirin, acting via RhoG in a novel manner, plays a central role in establishing the morphological phenotypic diversity that is essential to the connectivity of the developing nervous system.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alternative Splicing
  • Animals
  • Axons / drug effects
  • Axons / physiology*
  • Axons / ultrastructure
  • Carrier Proteins*
  • Cells, Cultured
  • GTP Phosphohydrolases / metabolism*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Guanine Nucleotide Exchange Factors / pharmacology
  • Microinjections
  • Nerve Fibers / drug effects
  • Nerve Fibers / physiology
  • Nerve Fibers / ultrastructure
  • Oligonucleotides, Antisense / pharmacology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Isoforms / pharmacology
  • Protein Structure, Tertiary / genetics
  • Protein Structure, Tertiary / physiology
  • Rats
  • Sympathetic Nervous System / cytology
  • Sympathetic Nervous System / drug effects
  • Sympathetic Nervous System / metabolism
  • cdc42 GTP-Binding Protein / metabolism
  • rac1 GTP-Binding Protein / metabolism


  • Carrier Proteins
  • Guanine Nucleotide Exchange Factors
  • Kalrn protein, rat
  • Oligonucleotides, Antisense
  • Protein Isoforms
  • Rhog protein, rat
  • GTP Phosphohydrolases
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein