Control of axonal branching and synapse formation by focal adhesion kinase.
The formation of neuronal networks in the central nervous system (CNS) requires precise control of axonal branch development and stabilization. Here we show that cell-specific ablation of the murine gene Ptk2 (more commonly known as fak), encoding focal adhesion kinase (FAK), increases the number of axonal terminals and synapses formed by neurons in vivo. Consistent with this, fak mutant neurons also form greater numbers of axonal branches in culture because they have increased branch formation and reduced branch retraction. Expression of wild-type FAK, but not that of several FAK variants that prevent interactions with regulators of Rho family GTPases including the p190 Rho guanine nuclear exchange factor (p190RhoGEF), rescues the axonal arborization phenotype observed in fak mutant neurons. In addition, expression of a mutant p190RhoGEF that cannot associate with FAK results in a phenotype very similar to that of neurons lacking FAK. Thus, FAK functions as a negative regulator of axonal branching and synapse formation, and it seems to exert its actions, in part, through Rho family GTPases.
Rico
Beatriz
B
Howard Hughes Medical Institute and Department of Physiology, University of California, San Francisco, California 94143, USA. brico@umh.es <brico@umh.es>
Beggs
Hilary E
HE
Schahin-Reed
Dorreyah
D
Kimes
Nikole
N
Schmidt
Andrea
A
Reichardt
Louis F
LF
D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D001921:Brain / Q000002:abnormalities* / Q000378:metabolism / Q000648:ultrastructure; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000002:abnormalities / Q000378:metabolism / Q000648:ultrastructure; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000235:genetics; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020690:GTPase-Activating Proteins; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000002:abnormalities / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012097:Repressor Proteins; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure
C513041:Arhgap35 protein, mouse; C513040:Arhgap35 protein, rat; C513042:Arhgap5 protein, mouse; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012097:Repressor Proteins; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; C496052:Ptk2 protein, rat