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Integrin β1 signals through Arg to regulate postnatal dendritic arborization, synapse density, and behavior.

Integrins are heterodimeric extracellular matrix receptors that are essential for the proper development of the vertebrate nervous system. We report here that selective loss of integrin β1 in excitatory neurons leads to reductions in the size and complexity of hippocampal dendritic arbors, hippocampal synapse loss, impaired hippocampus-dependent learning, and exaggerated psychomotor sensitivity to cocaine in mice. Our biochemical and genetic experiments demonstrate that the intracellular tail of integrin β1 binds directly to Arg kinase and that this interaction stimulates activity of the Arg substrate p190RhoGAP, an inactivator of the RhoA GTPase. Moreover, genetic manipulations that reduce integrin β1 signaling through Arg recapitulate the integrin β1 knock-out phenotype in a gene dose-sensitive manner. Together, these results describe a novel integrin β1-Arg-p190RhoGAP pathway that regulates dendritic arbor size, promotes synapse maintenance, supports proper hippocampal function, and mitigates the behavioral consequences of cocaine exposure.

Pubmed ID: 22357865

Authors

  • Warren MS
  • Bradley WD
  • Gourley SL
  • Lin YC
  • Simpson MA
  • Reichardt LF
  • Greer CA
  • Taylor JR
  • Koleske AJ

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

February 22, 2012

Associated Grants

  • Agency: NIAAA NIH HHS, Id: AA017537
  • Agency: NIA NIH HHS, Id: AG039124
  • Agency: NCI NIH HHS, Id: CA133346
  • Agency: NIDA NIH HHS, Id: DA011717
  • Agency: NIDCD NIH HHS, Id: DC00210
  • Agency: NIA NIH HHS, Id: F31 AG039124
  • Agency: NINDS NIH HHS, Id: NS058086
  • Agency: NINDS NIH HHS, Id: NS19090
  • Agency: NINDS NIH HHS, Id: NS39475
  • Agency: NCI NIH HHS, Id: R01 CA133346
  • Agency: NIDA NIH HHS, Id: R01 DA011717
  • Agency: NIDA NIH HHS, Id: R01 DA015222
  • Agency: NIDCD NIH HHS, Id: R01 DC000210
  • Agency: NIGMS NIH HHS, Id: R01 GM100411
  • Agency: NINDS NIH HHS, Id: R01 NS039475
  • Agency: NINDS NIH HHS, Id: R01 NS039475-09A1
  • Agency: NINDS NIH HHS, Id: R01 NS039475-10
  • Agency: NINDS NIH HHS, Id: R01 NS039475-11
  • Agency: NINDS NIH HHS, Id: R01 NS039475-11S1
  • Agency: NINDS NIH HHS, Id: R01 NS039475-12
  • Agency: NINDS NIH HHS, Id: R01 NS039475-13
  • Agency: NIGMS NIH HHS, Id: T32 GM007223

Mesh Terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Antigens, CD29
  • Avoidance Learning
  • Basic Helix-Loop-Helix Transcription Factors
  • Cells, Cultured
  • Cocaine
  • Dendrites
  • Enzyme-Linked Immunosorbent Assay
  • Exploratory Behavior
  • GTPase-Activating Proteins
  • Green Fluorescent Proteins
  • Hippocampus
  • Immunoprecipitation
  • Male
  • Mice
  • Mice, Knockout
  • Mutation
  • Nerve Tissue Proteins
  • Neurons
  • Organ Culture Techniques
  • Post-Synaptic Density
  • Protein Binding
  • Recognition (Psychology)
  • Repressor Proteins
  • Signal Transduction
  • Synapses
  • alpha-Fetoproteins
  • src Homology Domains