title: Integrin β1 signals through Arg to regulate postnatal dendritic arborization, synapse density, and behavior.
abstract: 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.
authors.affiliation: Department of Molecular Biophysics and Biochemistry,Yale University, New Haven, CT 06510, USA.
authors.forename: M Sloan
authors.initials: MS
authors.lastname: Warren
authors.forename: William D
authors.initials: WD
authors.lastname: Bradley
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Gourley
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Lin
authors.forename: Mark A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Louis F
authors.initials: LF
authors.lastname: Reichardt
authors.forename: Charles A
authors.initials: CA
authors.lastname: Greer
authors.forename: Jane R
authors.initials: JR
authors.lastname: Taylor
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Koleske
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency; D002478:Cells, Cultured; D003042:Cocaine / Q000008:administration & dosage; D003712:Dendrites / Q000378:metabolism* / Q000648:ultrastructure; D004797:Enzyme-Linked Immunosorbent Assay; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000648:ultrastructure; D047468:Immunoprecipitation; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000172:deficiency; D009474:Neurons / Q000166:cytology* / Q000502:physiology / Q000648:ultrastructure; D009924:Organ Culture Techniques; D057907:Post-Synaptic Density / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains / Q000187:drug effects / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003042:Cocaine; D020690:GTPase-Activating Proteins; D049452:Green Fluorescent Proteins; D019012:Integrin beta1; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D000509:alpha-Fetoproteins; C513041:Arhgap35 protein, mouse; C110701:Neurod6 protein, mouse; C545206:alpha-fetoprotein related protein, mouse