Synaptic protein DLG2 controls neurogenic transcriptional programs disrupted in schizophrenia and related disorders
Tom G. J. Steward,
Sophie E Legge,
Antonio F. Pardiñas,
Adrian J. Harwood,
William P. Gray,
Michael C O'Donovan,
Michael J Owen,
Adam C. Errington,
Derek J. Blake,
Daniel J. Whitcomb,
Andrew J. Pocklington,
Posted 10 Jan 2020
bioRxiv DOI: 10.1101/2020.01.10.898676
Posted 10 Jan 2020
Genetic studies robustly implicate perturbation of DLG2-scaffolded mature postsynaptic signalling complexes in schizophrenia. Here we study in vitro cortical differentiation of DLG2-/- human embryonic stem cells via integrated phenotypic, gene expression and disease genetic analyses. This uncovers a developmental role for DLG2 in the regulation of neural stem cell proliferation and adhesion, and the activation of transcriptional programs during early excitatory corticoneurogenesis. Down-regulation of these programs in DLG2-/- lines delays expression of cell-type identity and causes marked deficits in neuronal migration, morphology and active properties. Genetic risk factors for neuropsychiatric and neurodevelopmental disorders converge on these neurogenic programs, each disorder displaying a distinct pattern of enrichment. These data unveil an intimate link between neurodevelopmental and mature signalling deficits contributing to disease - suggesting a dual role for known synaptic risk genes - and reveal a common pathophysiological framework for studying the neurodevelopmental origins of Mendelian and genetically complex mental disorders.
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