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

Bret Sanders, Daniel D'Andrea, Mark O Collins, Elliott E 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 (+6 others)
2020 bioRxiv   pre-print
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.
more » ... on 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.
doi:10.1101/2020.01.10.898676 fatcat:vav4e3dufzc5pnaljai3ddjscm