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Author Notes:

Correspondence: Jennifer Larimore ; Email: jlarimore@agnesscott.edu

MA, RC, and KSS contributed equally to the manuscript and are co-first authors.

All authors contributed to the manuscript.

We thank Dr. Paul Randazzo (NIH) and Dr. Nie (NIH) for helpful discussions and AGAP1 antibodies, and Dr. Elizabeth Sztul (UAB) for useful discussions.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Research Funding:

This work was supported in part by the following awards: IRSF award, Civitan International Emerging Scholar Grant, and McKnight Brain Institute award to JL; NIH grant MH-50102, and McKnight Brain Institute Pilot Research Grant to AT; NIH grant GM-077569, and Neuroscience Center of Children’s Healthcare of Atlanta to VF; NIH grants NS-065027 and NS-40593 to LP-M; and by the Integrated Cellular Imaging Microscopy Core and the Viral Cores of the Emory Neuroscience NINDS Core Facilities (P30-NS-055077).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • AGAP1
  • Arf-GAP
  • autism
  • dendritic spines
  • dysbindin
  • endosome
  • schizophrenia
  • SUSCEPTIBILITY FACTOR DYSBINDIN
  • ORGANOTYPIC SLICE CULTURES
  • RECYCLING ENDOSOMES
  • NEUROPSYCHIATRIC DISORDERS
  • HIPPOCAMPAL-NEURONS
  • PYRAMIDAL NEURONS
  • PROTEIN COMPLEXES
  • MECP2 MUTATIONS
  • SCHIZOPHRENIA
  • PLASTICITY

The Endosome Localized Arf-GAP AGAP1 Modulates Dendritic Spine Morphology Downstream of the Neurodevelopmental Disorder Factor Dysbindin

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Journal Title:

Frontiers in Cellular Neuroscience

Volume:

Volume 10, Number SEP2016

Publisher:

, Pages 218-218

Type of Work:

Article | Final Publisher PDF

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 endosomedependent 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 the DTNBP1 gene, 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 of DTNBP1. We postulate that endosomal trafficking contributes to the pathogenesis of neurodevelopmental disorders affecting dendritic spine morphology, and thus excitatory synapse structure and function.

Copyright information:

© 2016 Arnold, Cross, Singleton, Zlatic, Chapleau, Mullin, Rolle, Moore, Theibert, Pozzo-Miller, Faundez and Larimore.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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