title: Cell migration in schizophrenia: Patient-derived cells do not regulate motility in response to extracellular matrix.
abstract: Schizophrenia is a highly heritable psychiatric disorder linked to a large number of risk genes. The function of these genes in disease etiology is not fully understood but pathway analyses of genomic data suggest developmental dysregulation of cellular processes such as neuronal migration and axon guidance. Previous studies of patient-derived olfactory cells show them to be more motile than control-derived cells when grown on a fibronectin substrate, motility that is dependent on focal adhesion kinase signaling. The aim of this study was to investigate whether schizophrenia patient-derived cells are responsive to other extracellular matrix (ECM) proteins that bind integrin receptors. Olfactory neurosphere-derived cells from nine patients and nine matched controls were grown on ECM protein substrates at increasing concentrations and their movement was tracked for 24h using automated high-throughput imaging. Control-derived cells increased their motility as the ECM substrate concentration increased, whereas patient-derived cell motility was little affected by ECM proteins. Patient and control cells had appropriate integrin receptors for these ECM substrates and detected them as shown by increases in focal adhesion number and size in response to ECM proteins, which also induced changes in cell morphology and cytoskeleton. These observations indicate that patient cells failed to translate the detection of ECM proteins into appropriate changes in cell motility. In a sense, patient cells act like a moving car whose accelerator is jammed, moving at the same speed without regard to the external environment. This focuses attention on cell motility regulation rather than speed as key to impairment of neuronal migration in the developing brain in schizophrenia.
authors.affiliation: Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
authors.forename: Jing Yang
authors.initials: JY
authors.lastname: Tee
authors.affiliation: Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
authors.forename: Ratneswary
authors.initials: R
authors.lastname: Sutharsan
authors.affiliation: Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia. Electronic address: a.mackay-sim@griffith.edu.au.
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay-Sim
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002460:Cell Line / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009831:Olfactory Mucosa / Q000473:pathology; D018034:Olfactory Receptor Neurons / Q000187:drug effects / Q000502:physiology*; D012559:Schizophrenia / Q000473:pathology*; D055815:Young Adult
chemical_list: D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins
keywords: Automated image analysis; Cell motility regulation; Extracellular matrix; Focal adhesion; Patient-derived cell; Schizophrenia