Cerebral organoids reveal early cortical maldevelopment in schizophrenia\u2014computational anatomy and genomics, role of FGFR1

E K Stachowiak,P Sarder,L E Bayona Chuye,A Dimitri,K Harikrishnan,D Freedman,C A Benson,K J Brennand,M K Stachowiak,S Dhiman,S T Narla,S Elahi

doi:10.1038/s41398-017-0054-x

E K Stachowiak, P Sarder + Show 10 more

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https://doi.org/10.1038/s41398-017-0054-x

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Abstract

Studies of induced pluripotent stem cells (iPSCs) from schizophrenia patients and control individuals revealed that the disorder is programmed at the preneuronal stage, involves a common dysregulated mRNA transcriptome, and identified Integrative Nuclear FGFR1 Signaling a common dysregulated mechanism. We used human embryonic stem cell (hESC) and iPSC-derived cerebral organoids from four controls and three schizophrenia patients to model the first trimester of in utero brain development. The schizophrenia organoids revealed an abnormal scattering of proliferating Ki67+ neural progenitor cells (NPCs) from the ventricular zone (VZ), throughout the intermediate (IZ) and cortical (CZ) zones. TBR1 pioneer neurons and reelin, which guides cortico-petal migration, were restricted from the schizophrenia cortex. The maturing neurons were abundantly developed in the subcortical regions, but were depleted from the schizophrenia cortex. The decreased intracortical connectivity was denoted by changes in the orientation and morphology of calretinin interneurons. In schizophrenia organoids, nuclear (n)FGFR1 was abundantly expressed by developing subcortical cells, but was depleted from the neuronal committed cells (NCCs) of the CZ. Transfection of dominant negative and constitutively active nFGFR1 caused widespread disruption of the neuro-ontogenic gene networks in hESC-derived NPCs and NCCs. The fgfr1 gene was the most prominent FGFR gene expressed in NPCs and NCCs, and blocking with PD173074 reproduced both the loss of nFGFR1 and cortical neuronal maturation in hESC cerebral organoids. We report for the first time, progression of the cortical malformation in schizophrenia and link it to altered FGFR1 signaling. Targeting INFS may offer a preventive treatment of schizophrenia.

Highlights

The primary onset of schizophrenia is during adolescence to young adulthood, an early developmental origin of schizophrenia has been implied by improperly clustered immature neurons in cortical layers II, III, and V1, changes in the hippocampal nonpyramidal CA2neurons[2], as well as hypoplastic midbrain dopamine neurons[3,4,5,6]
The cerebral organoid technology applied to control and schizophrenia iPSCs29,31,33 provided for the first time, an insight into the early stages of the telencephalic development and the role of FGFR1 in schizophrenia. These results showed an abnormal dispersion of the proliferating stem-like cells outside the ventricular zone (VZ) into the intermediate zone (IZ) and cortical zone (CZ), and a curtailed neuronal cortical development in the CZ of the schizophrenia cerebral organoids accompanied by turning off the expression of nuclear FGFR1 (nFGFR1)
An important observation made repeatedly during this study was that the cellular structures and zones of the organoid rosettes and their development were consistently reproducible among human embryonic stem cell (hESC) H9, HUES8, and the four control induced pluripotent stem cells (iPSCs) line organoids, but were noticeably disturbed in all schizophrenia iPSC organoids and after

Summary

Introduction

The primary onset of schizophrenia is during adolescence to young adulthood, an early developmental origin of schizophrenia has been implied by improperly clustered immature neurons in cortical layers II, III, and V1, changes in the hippocampal nonpyramidal CA2neurons[2], as well as hypoplastic midbrain dopamine neurons[3,4,5,6]. In the developing vertebrate brain, the elongated bipolar radial glia are located at the apical surface of the ventricular zone (VZ) and span the width of the cortex These cells generate translocating radial glia, intermediate progenitor cells, and neuroblasts that migrate through the intermediate zone (IZ) to the outer cortical zone (CZ), and populate cortical layers. Via this inside-out process, the early born neurons occupy inner layers while the late born neurons migrate out toward the edge and occupy the superficial cortical layers[15]. Disruption of these processes has been hypothesized to underlie the misconstruction of the cortex and subcortical circuits observed in autism[16] and schizophrenia (review-17)

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