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Patient Cells Shed Light On Developmental Mechanisms Underlying Schizophrenia

Although schizophrenia is not usually manifest until adolescence or early adulthood, current theories suggest there are neurodevelopmental defects that occur in utero during formation of the brain that underlie the disease. In order to understand the basis of the defects, Dr. Michal Stachowiak from the University at Buffalo collaborated with Dr. Kristen Brennand at the Icahn School of Medicine at Mount Sinai to examine stem cells derived from schizophrenia patients. Dr. Brennand had previously generated induced pluripotent stem cells (iPSCs), cells that are similar to human embryonic stem cells, from several schizophrenia patients. Her prior work showed that differentiation into mature neurons was different between patient and control cells. Now Dr. Stachowiak’s research group analyzed less differentiated neurons, neuron committed cells (NCCs), and reports finding differences at this earlier developmental stage. Their results indicate that there is global dysregulation of developmental gene expression networks in the cells of schizophrenia patients and establishment of new, aberrant networks. Importantly, the dysregulation was observed in cells from all four unrelated schizophrenia patients tested, suggesting it is a common feature of the disease. A key molecule in establishing the new aberrant networks is nFGFR1, the nuclear form of fibroblast growth factor receptor 1. nFGFR1 regulates a number of different pathways in normal cells, but is overexpressed in NCCs from schizophrenic patients. This overexpression appears to favor differentiation of the neural progenitors into neurons and away from glial cells, perhaps explaining why post-mortem analysis of schizophrenia patients shows increased numbers of neurons and other abnormalities in the central nervous system. This research was supported in part by a NYSTEM research award to Dr. Stachowiak (C026415) and a shared facilities award to the University at Buffalo (C026714) and by the Patrick P. Lee Foundation.

Narla ST, Lee YW, Benson CA, Sarder P, Brennand KJ, Stachowiak EK, Stachowiak MK. Common developmental genome deprogramming in schizophrenia - Role of Integrative Nuclear FGFR1 Signaling (INFS). Schizophrenia Research. 2017 Jan 13.