title: The Endosome Localized Arf-GAP AGAP1 Modulates Dendritic Spine Morphology Downstream of the Neurodevelopmental Disorder Factor Dysbindin.
abstract: AGAP1 is an Arf1 GTPase activating protein that interacts with the vesicle-associated protein complexes adaptor protein 3 (AP-3) and Biogenesis of Lysosome Related Organelles Complex-1 (BLOC-1). Overexpression of AGAP1 in non-neuronal cells results in an accumulation of endosomal cargoes, which suggests a role in endosome-dependent traffic. In addition, AGAP1 is a candidate susceptibility gene for two neurodevelopmental disorders, autism spectrum disorder (ASD) and schizophrenia (SZ); yet its localization and function in neurons have not been described. Here, we describe that AGAP1 localizes to axons, dendrites, dendritic spines and synapses, colocalizing preferentially with markers of early and recycling endosomes. Functional studies reveal overexpression and down-regulation of AGAP1 affects both neuronal endosomal trafficking and dendritic spine morphology, supporting a role for AGAP1 in the recycling endosomal trafficking involved in their morphogenesis. Finally, we determined the sensitivity of AGAP1 expression to mutations in theDTNBP1gene, which is associated with neurodevelopmental disorder, and found that AGAP1 mRNA and protein levels are selectively reduced in the null allele of the mouse ortholog ofDTNBP1. We postulate that endosomal trafficking contributes to the pathogenesis of neurodevelopmental disorders affecting dendritic spine morphology, and thus excitatory synapse structure and function.
authors.affiliation: Department of Biology, Agnes-Scott College Decatur, GA, USA.
authors.forename: Miranda
authors.initials: M
authors.lastname: Arnold
authors.affiliation: Department of Biology, Agnes-Scott College Decatur, GA, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cross
authors.affiliation: Interdisciplinary Program in Neuroscience, Georgetown University Washington, DC, USA.
authors.forename: Kaela S
authors.initials: KS
authors.lastname: Singleton
authors.affiliation: Department of Cell Biology, Emory University Atlanta, GA, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zlatic
authors.affiliation: Department of Neurobiology, Civitan International Research Center, University of Alabama Birmingham, AL, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chapleau
authors.affiliation: Acorda Therapeutics New York, NY, USA.
authors.forename: Ariana P
authors.initials: AP
authors.lastname: Mullin
authors.affiliation: Heritage College of Osteopathic Medicine, The Medical School of Ohio University Athens, OH, USA.
authors.forename: Isaiah
authors.initials: I
authors.lastname: Rolle
authors.affiliation: Department of Neurobiology, Civitan International Research Center, University of Alabama Birmingham, AL, USA.
authors.forename: Carlene C
authors.initials: CC
authors.lastname: Moore
authors.affiliation: Department of Neurobiology, Civitan International Research Center, University of Alabama Birmingham, AL, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Theibert
authors.affiliation: Department of Neurobiology, Civitan International Research Center, University of Alabama Birmingham, AL, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Pozzo-Miller
authors.affiliation: Department of Cell Biology, Emory University Atlanta, GA, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Faundez
authors.affiliation: Department of Biology, Agnes-Scott College Decatur, GA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Larimore
keywords: AGAP1; Arf-GAP; autism; dendritic spines; dysbindin; endosome; schizophrenia