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DLG2 knockout reveals neurogenic transcriptional programs underlying neuropsychiatric disorders and cognition

ABSTRACT: A complex train of events unfolds during brain development, guided by activation/repression of gene expression programs. It remains unclear how this process is disrupted in disease. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. This reveals a cascade of transcriptional programs activated during early corticoneurogenesis in vitro and in vivo. Genetic variation in these programs is robustly associated with neuropsychiatric disorders and cognitive function, with variants concentrated in loss-of-function intolerant genes. Neurogenic programs also capture schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways activated during pre-natal development underlie disease-relevant deficits in mature neuronal function. Down-regulation of these programs in DLG2-/- lines delays expression of cell-type identity and impairs neuronal migration, morphology and action potential generation, validating predicted deficits. These data implicate specific cellular pathways underlying neurodevelopment in the aetiology of multiple neuropsychiatric disorders and cognition.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neuronal Stem Cell

SUBMITTER: Mark Collins

LAB HEAD: Mark O Collins

PROVIDER: PXD029526 | Pride | 2021-11-11

REPOSITORIES: Pride

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DLG2 knockout reveals neurogenic transcriptional programs underlying neuropsychiatric disorders and cognition

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