title: Dynamic recruitment of the curvature-sensitive protein ArhGAP44 to nanoscale membrane deformations limits exploratory filopodia initiation in neurons.
abstract: In the vertebrate central nervous system, exploratory filopodia transiently form on dendritic branches to sample the neuronal environment and initiate new trans-neuronal contacts. While much is known about the molecules that control filopodia extension and subsequent maturation into functional synapses, the mechanisms that regulate initiation of these dynamic, actin-rich structures have remained elusive. Here, we find that filopodia initiation is suppressed by recruitment of ArhGAP44 to actin-patches that seed filopodia. Recruitment is mediated by binding of a membrane curvature-sensing ArhGAP44 N-BAR domain to plasma membrane sections that were deformed inward by acto-myosin mediated contractile forces. A GAP domain in ArhGAP44 triggers local Rac-GTP hydrolysis, thus reducing actin polymerization required for filopodia formation. Additionally, ArhGAP44 expression increases during neuronal development, concurrent with a decrease in the rate of filopodia formation. Together, our data reveals a local auto-regulatory mechanism that limits initiation of filopodia via protein recruitment to nanoscale membrane deformations.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, United States.
authors.forename: Milos
authors.initials: M
authors.lastname: Galic
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, United States.
authors.forename: Feng-Chiao
authors.initials: FC
authors.lastname: Tsai
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, United States.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Collins
authors.affiliation: Department of Pathology, Stanford University, Stanford, United States.
authors.forename: Maja
authors.initials: M
authors.lastname: Matis
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, United States.
authors.forename: Samuel
authors.initials: S
authors.lastname: Bandara
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, United States.
authors.forename: Tobias
authors.initials: T
authors.lastname: Meyer
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D008954:Models, Biological; D009218:Myosins / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism*; D017208:Rats, Wistar; D012015:Reference Standards; D013116:Spinal Cord / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C000600214:ArhGAP44 protein, rat; D020690:GTPase-Activating Proteins; D009218:Myosins; D020830:rac1 GTP-Binding Protein
keywords: actin; cell biology; membrane curvature; neuron; rat