Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants

Abstract

Coordinated programs of gene expression drive brain development. It is unclear which transcriptional programs, in which cell-types, are affected in neuropsychiatric disorders such as schizophrenia. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. We identify transcriptional programs expressed during early neurogenesis in vitro and in human foetal cortex that are down-regulated in DLG2−/− lines. Down-regulation impacted neuronal differentiation and maturation, impairing migration, morphology and action potential generation. Genetic variation in these programs is associated with neuropsychiatric disorders and cognitive function, with associated variants predominantly concentrated in loss-of-function intolerant genes. Neurogenic programs also overlap schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways active during prenatal cortical development may also be associated with mature neuronal dysfunction. Our data from human embryonic stem cells, when combined with analysis of available foetal cortical gene expression data, de novo rare variants and GWAS statistics for neuropsychiatric disorders and cognition, reveal a convergence on transcriptional programs regulating excitatory cortical neurogenesis.

Comprehensive network modeling approaches unravel dynamic enhancer-promoter interactions across neural differentiation

“…MDD-associated SNVs, PD-associated SNVs, and AD-associated SNVs were deemed non-significant. These findings suggest our E-P-INs capture enhancers relevant to neural differentiation; SCZ and BD are disorders with neurodevelopmental origins [22, 23]. Out of the 1,592 enhancers considered in our collapsed E-P-IN, 140 contain either a case or control de novo variant for ASD, with case variants favored; 27 contain a GWAS-sourced SNV for a neurological/neuropsychiatric disorder.…”

RFX4 is an intrinsic factor for neuronal differentiation through induction of proneural genes POU3F2 and NEUROD1

“…However, although there have been numerous studies on the external factors that induce neuronal differentiation, little is known about the factors that intrinsically induce the expression of these proneural factors. The research on the neural differentiation mechanism has been enhancing our understanding of neuropsychiatric disorders originating from various neurodevelopmental origins, which include schizophrenia, depression, autism spectrum disorder, and bipolar disorders [15]. Especially, various in vitro models are developed with iPSC to investigate the molecular pathogenesis of neuropsychiatric disorders [16].…”

A mild impairment in reversal learning in a bowl‐digging substrate deterministic task but not other cognitive tests in the Dlg2+/− rat model of genetic risk for psychiatric disorder

“… 7 , 8 The PSD93 protein is expressed widely throughout the brain 9 , 10 , 11 and has been demonstrated to interact with a variety of other proteins in the postsynaptic density, including NMDAR receptor subunits, 12 , 13 , 14 , 15 , 16 AMPAR auxiliary subunit stargazin, 17 potassium channels, 18 , 19 , 20 , 21 and other cytoskeletal components. 12 , 22 , 23 , 24 , 25 , 26 Work on homozygous knockout rodents models of Dlg2−/− has found evidence of deficits in glutamatergic signalling, 10 , 14 , 27 , 28 , 29 , 30 , 31 plasticity, 28 and dendritic 32 and spine 31 morphology in the hippocampus, dorsal striatum, spinal dorsal horn, and cingular and visual cortices. We have recently demonstrated in the heterozygous rat Dlg2+/− model hippocampal CA1 pyramidal neurons enhanced NMDA receptor currents, reduced input resistance, reduced dendritic arborisation, impaired dendritic integration, and associative plasticity.…”