Neuregulin1-induced cell migration is impaired in schizophrenia: association with neuregulin1 and catechol-o-methyltransferase gene polymorphisms.
Neuregulin1 (NRG1), a candidate susceptibility gene for schizophrenia, plays a critical role in neuronal migration and central nervous system development. However, its relation to schizophrenia pathogenesis is unknown. Here we show that B lymphoblasts migrate to NRG1 through the ErbB-signaling system as observed in neuronal cells. We assessed NRG1-induced cell migration in B lymphoblasts from patients with schizophrenia and found that NRG1-induced migration is significantly decreased compared with control individuals in two independent cohorts. This impaired migration is related at least in part to reduced AKT phosphorylation in the patients. Moreover, the magnitude of NRG1-induced migration is associated with polymorphisms of the NRG1 and catechol-o-methyltransferase genes and with an epistatic interaction of these genes. This study demonstrates that the migratory response of schizophrenia-derived cells to NRG1 is impaired and is associated with genetic variations in more than one schizophrenia susceptibility gene, providing a novel insight into potential neurodevelopmental mechanisms of schizophrenia.
Sei
Y
Y
Clinical Brain Disorder Branch, Genes, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1385, USA. seiy@mail.nih.gov
Ren-Patterson
R
R
Li
Z
Z
Tunbridge
E M
EM
Egan
M F
MF
Kolachana
B S
BS
Weinberger
D R
DR
D000328:Adult; D000704:Analysis of Variance; D001402:B-Lymphocytes / Q000187:drug effects*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D020890:Neuregulin-1 / Q000235:genetics* / Q000494:pharmacology*; D011110:Polymorphism, Genetic / Q000187:drug effects*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D018709:Statistics, Nonparametric
D002394:Catechol O-Methyltransferase; D004791:Enzyme Inhibitors; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3