Growth arrest specific gene 7 is associated with schizophrenia and regulates neuronal migration and morphogenesis

Mol Brain. 2016 May 18;9(1):54. doi: 10.1186/s13041-016-0238-y.

Abstract

Background: Schizophrenia is a highly heritable chronic mental disorder with significant abnormalities in brain function. The neurodevelopmental hypothesis proposes that schizophrenia originates in the prenatal period due to impairments in neuronal developmental processes such as migration and arborization, leading to abnormal brain maturation. Previous studies have identified multiple promising candidate genes that drive functions in neurodevelopment and are associated with schizophrenia. However, the molecular mechanisms of how they exert effects on the pathophysiology of schizophrenia remain largely unknown.

Results: In our research, we identified growth arrest specific gene 7 (GAS7) as a schizophrenia risk gene in two independent Han Chinese populations using a two-stage association study. Functional experiments were done to further explore the underlying mechanisms of the role of Gas7 in cortical development. In vitro, we discovered that Gas7 contributed to neurite outgrowth through the F-BAR domain. In vivo, overexpression of Gas7 arrested neuronal migration by increasing leading process branching, while suppression of Gas7 could inhibit neuronal migration by lengthening leading processes. Through a series of behavioral tests, we also found that Gas7-deficient mice showed sensorimotor gating deficits.

Conclusions: Our results demonstrate GAS7 as a susceptibility gene for schizophrenia. Gas7 might participate in the pathogenesis of schizophrenia by regulating neurite outgrowth and neuronal migration through its C-terminal F-BAR domain. The impaired pre-pulse inhibition (PPI) of Gas7-deficient mice might mirror the disease-related behavior in schizophrenia.

Keywords: GAS7; Neurite outgrowth; Neuronal migration; Schizophrenia.

MeSH terms

  • Adult
  • Animals
  • Cell Movement*
  • Female
  • Gene Knockdown Techniques
  • Genetic Association Studies*
  • Genetic Markers
  • Genetic Predisposition to Disease*
  • HEK293 Cells
  • Humans
  • Male
  • Mice, Inbred ICR
  • Morphogenesis*
  • Mutant Proteins / metabolism
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurites / metabolism
  • Neurons / metabolism*
  • Neurons / pathology*
  • Polymorphism, Single Nucleotide / genetics
  • Prepulse Inhibition / genetics
  • Protein Domains
  • Pseudopodia / metabolism
  • Pyramidal Cells / metabolism
  • Schizophrenia / genetics*
  • Schizophrenia / physiopathology

Substances

  • GAS7 protein, human
  • Gas7 protein, mouse
  • Genetic Markers
  • Mutant Proteins
  • Nerve Tissue Proteins