title: Growth arrest specific gene 7 is associated with schizophrenia and regulates neuronal migration and morphogenesis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute of Mental Health, The Sixth Hospital, Peking University, 51 Hua Yuan Bei Road, Hai Dian District, Beijing, 100191, China.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, 100191, China.
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Mental Health, The Sixth Hospital, Peking University, 51 Hua Yuan Bei Road, Hai Dian District, Beijing, 100191, China. fanfan.zheng@nlpr.ia.ac.cn.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, 100191, China. fanfan.zheng@nlpr.ia.ac.cn.|Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, 95 Zhong Guan Cun East Road, Hai Dian District, Beijing, 100190, China. fanfan.zheng@nlpr.ia.ac.cn.
authors.forename: Fanfan
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Institute of Mental Health, The Sixth Hospital, Peking University, 51 Hua Yuan Bei Road, Hai Dian District, Beijing, 100191, China.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, 100191, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: You
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China.|PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China.
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Institute of Mental Health, The Sixth Hospital, Peking University, 51 Hua Yuan Bei Road, Hai Dian District, Beijing, 100191, China.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, 100191, China.
authors.forename: Tianlan
authors.initials: T
authors.lastname: Lu
authors.affiliation: Institute of Mental Health, The Sixth Hospital, Peking University, 51 Hua Yuan Bei Road, Hai Dian District, Beijing, 100191, China.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, 100191, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Yue
authors.affiliation: Institute of Mental Health, The Sixth Hospital, Peking University, 51 Hua Yuan Bei Road, Hai Dian District, Beijing, 100191, China. daizhang@bjmu.edu.cn.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, 100191, China. daizhang@bjmu.edu.cn.|Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China. daizhang@bjmu.edu.cn.|PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China. daizhang@bjmu.edu.cn.
authors.forename: Dai
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000818:Animals; D002465:Cell Movement; D005260:Female; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008813:Mice, Inbred ICR; D009024:Morphogenesis; D050505:Mutant Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D065808:Prepulse Inhibition / Q000235:genetics; D000072417:Protein Domains; D011554:Pseudopodia / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology
chemical_list: C114909:GAS7 protein, human; C485435:Gas7 protein, mouse; D005819:Genetic Markers; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins
keywords: GAS7; Neurite outgrowth; Neuronal migration; Schizophrenia