Induced Pluripotent Stem Cells Reveal Common Neurodevelopmental Genome Deprograming in Schizophrenia

Abstract

Schizophrenia is a neurodevelopmental disorder characterized by complex aberrations in the structure, wiring, and chemistry of multiple neuronal systems. The abnormal developmental trajectory of the brain is established during gestation, long before clinical manifestation of the disease. Over 200 genes and even greater numbers of single nucleotide polymorphisms and copy number variations have been linked with schizophrenia. How does altered function of such a variety of genes lead to schizophrenia? We propose that the protein products of these altered genes converge on a common neurodevelopmental pathway responsible for the development of brain neural circuit and neurotransmitter systems. The results of a multichanneled investigation using induced pluripotent stem cell (iPSCs)- and embryonic stem cell (ESCs)-derived neuronal committed cells (NCCs) indicate an early (preneuronal) developmental-genomic etiology of schizophrenia and that the dysregulated developmental gene networks are common to genetically unrelated cases of schizophrenia. The results support a "watershed" mechanism in which mutations within diverse signaling pathways affect the common pan-ontogenic mechanism, integrative nuclear (n)FGFR1 signaling (INFS). Dysregulation of INFS in schizophrenia NCCs deconstructs coordinated gene networks and leads to formation of new networks by the dysregulated genes. This genome deprograming affects critical gene programs and pathways for neural development and functions. Studies show that the genomic deprograming reflect an altered nFGFR1-genome interactions and deregulation of miRNA genes by nFGFR1. In addition, changes in chromatin topology imposed by nFGFR1 may play a role in coordinate gene dysregulation in schizophrenia.

Immune Factor, TNFα, Disrupts Human Brain Organoid Development Similar to Schizophrenia—Schizophrenia Increases Developmental Vulnerability to TNFα

“…In all conditions that led to cortical underdevelopment (SZ, C+TNF, SZ+TNF), the paucity of the cell bodies was accompanied by increased spaces between cells that were ''vacant'' in C+TNF but became filled with the ECM fibrous material in SZ and in SZ+TNF organoids. This suggests that SZ promotes ECM development, consistent with the presence of ECM regulating genes within the SZ dysregulated transcriptome (Narla et al, 2018). Such changes may alter the mechanical properties (surface tension) of the developing cortex, which could further influence the development of the brain cortex (Kroenke and Bayly, 2018) and, potentially, lead to mild cerebral atrophy observed in SZ patients (Weinberger et al, 1979).…”

“…The study by Narla et al ( 2017 , 2018 ) identified genes dysregulated in SZ NPC as belonging to the general Gene Ontology categories of neuronal development (overexpressed genes) and oligodendrogenesis (underexpressed genes). The exemplary genes of these two categories were found to be affected by nFGFR1: stimulated (neuronal genes: TH, DISC1, Wnt7B, NeuroD) and inhibited (oligodendrocytic genes: Olig 2, Olig 1; Narla et al, 2017 ).…”

“…The RNAseq analysis was performed in our earlier study (Narla et al, 2017 , 2018 ) using homogenous cultures of NPC differentiated from four control and four SZ patients’ iPSC lines. To induce neuronal committed cells, NPC were treated with 20 ng ml −1 BDNF (Peprotech), 20 ng ml −1 GDNF (Peprotech), 1 mM dibutyryl-cyclic AMP (Sigma), and 200 nM ascorbic acid (Sigma; Narla et al, 2017 ) for 2 days.…”

“…In parallel, these signals are fed forward by nFGFR1 directly to CREB binding protein (CBP), allowing genes to respond in a coordinated manner (Stachowiak and Stachowiak, 2016 ). Evidence indicates that in SZ, mutations of genes in diverse signaling pathways integrated by nFGFR1 disrupt the INFS function and thus neural development (Narla et al, 2018 ). Whether pathological environmental factors that contribute to SZ also affect nFGFR1, developmental function is unknown.…”

“…The cerebral organoids allowed for the first time to relate the broad INFS-linked transcriptional dysregulations found in SZ iPSC neural progenitor cells (NPCs; Narla et al, 2017 ) to development of the human brain malformations in SZ phenotype (Stachowiak et al, 2017 ). These genomic and tissue structural dysregulations were found in patients with different genomic backgrounds and may constitute a common developmental signature of the SZ phenotype (Chuye et al, 2018 ; Narla et al, 2018 ).…”