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Altered WNT Signaling in Human Induced Pluripotent Stem Cell Neural Progenitor Cells Derived from Four Schizophrenia Patients

      Schizophrenia (SZ) is a devastating psychiatric disorder hypothesized to be a neurodevelopmental condition (
      • Weinberger D.R.
      Implications of normal brain development for the pathogenesis of schizophrenia.
      ,
      • Marin O.
      • Baker J.
      • Puelles L.
      • Rubenstein J.L.
      Patterning of the basal telencephalon and hypothalamus is essential for guidance of cortical projections.
      ) arising as a consequence of dysregulation of brain development (
      • Guilmatre A.
      • Dubourg C.
      • Mosca A.L.
      • Legallic S.
      • Goldenberg A.
      • Drouin-Garraud V.
      • et al.
      Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation.
      ,
      • Jarskog L.F.
      • Miyamoto S.
      • Lieberman J.A.
      Schizophrenia: New pathological insights and therapies.
      ). WNT signaling is important for neural patterning, proliferation and migration, and synapse formation (
      • Gage F.H.
      Molecular and cellular mechanisms contributing to the regulation, proliferation and differentiation of neural stem cells in the adult dentate gyrus.
      ); converging postmortem (
      • Pietersen C.Y.
      • Mauney S.A.
      • Kim S.S.
      • Passeri E.
      • Lim M.P.
      • Rooney R.J.
      • et al.
      Molecular profiles of parvalbumin-immunoreactive neurons in the superior temporal cortex in schizophrenia.
      ,
      • Cotter D.
      • Kerwin R.
      • al-Sarraji S.
      • Brion J.P.
      • Chadwich A.
      • Lovestone S.
      • et al.
      Abnormalities of Wnt signalling in schizophrenia—evidence for neurodevelopmental abnormality.
      ), rodent (
      • Durak O.
      • de Anda F.C.
      • Singh K.K.
      • Leussis M.P.
      • Petryshen T.L.
      • Sklar P.
      • et al.
      Ankyrin-G regulates neurogenesis and Wnt signaling by altering the subcellular localization of beta-catenin [published online ahead of print May 13].
      ,
      • Singh K.K.
      • Ge X.
      • Mao Y.
      • Drane L.
      • Meletis K.
      • Samuels B.A.
      • et al.
      Dixdc1 is a critical regulator of DISC1 and embryonic cortical development.
      ), and pharmacologic (
      • Sutton L.P.
      • Rushlow W.J.
      Regulation of Akt and Wnt signaling by the group II metabotropic glutamate receptor antagonist LY341495 and agonist LY379268.
      ) evidence suggests that WNT signaling may contribute to SZ (
      • Hur E.M.
      • Zhou F.Q.
      GSK3 signalling in neural development.
      ,
      • Freyberg Z.
      • Ferrando S.J.
      • Javitch J.A.
      Roles of the Akt/GSK-3 and Wnt signaling pathways in schizophrenia and antipsychotic drug action.
      ). We used human induced pluripotent stem cell (hiPSC) derived forebrain patterned neural progenitor cells (NPCs) (
      • Brennand K.
      • Savas J.N.
      • Kim Y.
      • Tran N.
      • Simone A.
      • Hashimoto-Torii K.
      • et al.
      Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia [published online ahead of print Apr 1].
      ,
      • Brennand K.J.
      • Simone A.
      • Jou J.
      • Gelboin-Burkhart C.
      • Tran N.
      • Sangar S.
      • et al.
      Modelling schizophrenia using human induced pluripotent stem cells.
      ) to investigate canonical WNT activity in a pilot cohort of four patients with SZ.
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