PlexinA2 Forward Signaling through Rap1 GTPases Regulates Dentate Gyrus Development and Schizophrenia-like Behaviors

Xiao-Feng Zhao; Rafi Kohen; Rachel Parent; Yuntao Duan; Grace L Fisher; Matthew J Korn; Lingchao Ji; Guoqiang Wan; Jing Jin; Andreas W Püschel; David F Dolan; Jack M Parent; Gabriel Corfas; Geoffrey G Murphy; Roman J Giger

doi:10.1016/j.celrep.2017.12.044

PlexinA2 Forward Signaling through Rap1 GTPases Regulates Dentate Gyrus Development and Schizophrenia-like Behaviors

Cell Rep. 2018 Jan 9;22(2):456-470. doi: 10.1016/j.celrep.2017.12.044.

Authors

Xiao-Feng Zhao¹, Rafi Kohen², Rachel Parent³, Yuntao Duan¹, Grace L Fisher³, Matthew J Korn⁴, Lingchao Ji⁵, Guoqiang Wan⁵, Jing Jin⁶, Andreas W Püschel⁶, David F Dolan⁵, Jack M Parent⁷, Gabriel Corfas⁸, Geoffrey G Murphy⁹, Roman J Giger¹⁰

Affiliations

¹ Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
³ Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Institut für Molekulare Zellbiologie, Westfälische Wilhelms-Universität, 48149 Münster, Germany; Cells-in-Motion Cluster of Excellence, University of Münster, 48149 Münster, Germany.
⁷ Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
⁸ Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI 48109, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
⁹ Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁰ Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: rgiger@umich.edu.

Abstract

Dentate gyrus (DG) development requires specification of granule cell (GC) progenitors in the hippocampal neuroepithelium, as well as their proliferation and migration into the primordial DG. We identify the Plexin family members Plxna2 and Plxna4 as important regulators of DG development. Distribution of immature GCs is regulated by Sema5A signaling through PlxnA2 and requires a functional PlxnA2 GTPase-activating protein (GAP) domain and Rap1 small GTPases. In adult Plxna2^-/- but not Plxna2-GAP-deficient mice, the dentate GC layer is severely malformed, neurogenesis is compromised, and mossy fibers form aberrant synaptic boutons within CA3. Behavioral studies with Plxna2^-/- mice revealed deficits in associative learning, sociability, and sensorimotor gating-traits commonly observed in neuropsychiatric disorder. Remarkably, while morphological defects are minimal in Plxna2-GAP-deficient brains, defects in fear memory and sensorimotor gating persist. Since allelic variants of human PLXNA2 and RAP1 associate with schizophrenia, our studies identify a biochemical pathway important for brain development and mental health.

Keywords: GAP; PlexinA2; Rap1; adult neurogenesis; dentate gyrus; fear memory; mossy fiber; schizophrenia; semaphoring; sensorimotor gating.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dentate Gyrus / growth & development*
GTP Phosphohydrolases / genetics*
Humans
Mice
Nerve Tissue Proteins / genetics*
Nerve Tissue Proteins / metabolism*
Receptors, Cell Surface / genetics*
Receptors, Cell Surface / metabolism*
Schizophrenia / genetics*
Schizophrenia / metabolism
Signal Transduction

Substances

Nerve Tissue Proteins
Plxna2 protein, mouse
Receptors, Cell Surface
GTP Phosphohydrolases

Abstract

Publication types

MeSH terms

Substances

Grants and funding