NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice

Brain. 2018 Sep 1;141(9):2772-2794. doi: 10.1093/brain/awy190.

Abstract

Autism spectrum disorders are neurodevelopmental conditions with diverse aetiologies, all characterized by common core symptoms such as impaired social skills and communication, as well as repetitive behaviour. Cell adhesion molecules, receptor tyrosine kinases and associated downstream signalling have been strongly implicated in both neurodevelopment and autism spectrum disorders. We found that downregulation of the cell adhesion molecule NEGR1 or the receptor tyrosine kinase fibroblast growth factor receptor 2 (FGFR2) similarly affects neuronal migration and spine density during mouse cortical development in vivo and results in impaired core behaviours related to autism spectrum disorders. Mechanistically, NEGR1 physically interacts with FGFR2 and modulates FGFR2-dependent extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signalling by decreasing FGFR2 degradation from the plasma membrane. Accordingly, FGFR2 overexpression rescues all defects due to Negr1 knockdown in vivo. Negr1 knockout mice present phenotypes similar to Negr1-downregulated animals. These data indicate that NEGR1 and FGFR2 cooperatively regulate cortical development and suggest a role for defective NEGR1-FGFR2 complex and convergent downstream ERK and AKT signalling in autism spectrum disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autism Spectrum Disorder / metabolism
  • Autism Spectrum Disorder / physiopathology*
  • Behavior, Animal / physiology
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Cell Adhesion Molecules, Neuronal / physiology*
  • Cell Membrane / metabolism
  • Cell Movement
  • Cerebral Cortex / growth & development
  • Dendritic Spines / physiology
  • Disease Models, Animal
  • Down-Regulation
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurogenesis
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism
  • Receptor, Fibroblast Growth Factor, Type 2 / physiology*
  • Signal Transduction / physiology

Substances

  • Cell Adhesion Molecules, Neuronal
  • NEGR1 protein, mouse
  • Fgfr2 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 2