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Synaptic protein DLG2 controls neurogenic transcriptional programs disrupted in schizophrenia and related disorders

By Bret Sanders, Daniel D’Andrea, Mark O. Collins, Elliott Rees, Tom G. J. Steward, Ying Zhu, Gareth Chapman, 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, Eunju Shin

Posted 10 Jan 2020
bioRxiv DOI: 10.1101/2020.01.10.898676

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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