GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders

Lopez-Tobon, A.; Shyti, R.; Villa, C. E.; Cheroni, C.; Fuentes-Bravo, P.; Trattaro, S.; Caporale, N.; Troglio, F.; Tenderini, E.; Mihailovich, M.; Skaros, A.; Gibson, W. T.; Cuomo, A.; Bonaldi, T.; Mercurio, C.; Varasi, M.; Osborne, L. R.; Testa, G.

doi:10.1101/2022.10.10.511434

bioRxiv · 10.1101/2022.10.10.511434

GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders

Lopez-Tobon, A.·Shyti, R.·Villa, C. E.·Cheroni, C.·Fuentes-Bravo, P.·Trattaro, S.·Caporale, N.·Troglio, F.·Tenderini, E.·Mihailovich, M.·Skaros, A.·Gibson, W. T.·Cuomo, A.·Bonaldi, T.·Mercurio, C.·Varasi, M.·Osborne, L. R.·Testa, G.

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Abstract

Copy number variations at 7q11.23 cause neurodevelopmental disorders with shared and opposite manifestations. Deletion causes Williams-Beuren syndrome (WBS), while duplication causes 7q11.23 microduplication syndrome (7Dup). Converging evidence indicates GTF2I, from the 7q11.23 locus, is a key mediator of the cognitive-behavioral phenotypes associated with WBS and 7Dup. Here we integrate molecular profiling of patient-derived cortical organoids (COs) and transgenic mouse models to dissect 7q11.23 disease mechanisms. Proteomic and transcriptomic profiling of COs revealed opposite dynamics of neural progenitor proliferation and transcriptional imbalances, leading to precocious excitatory neuron production in 7Dup. The accelerated excitatory neuron production in 7Dup COs could be rescued by GTF2I knockdown. Transgenic mice with Gtf2i duplication recapitulated early neuronal differentiation defects and ASD-like behaviors. Remarkably, inhibition of LSD1, a downstream effector of GTF2I, was sufficient to rescue ASD-like phenotypes. We propose that the GTF2I-LSD1 axis constitutes a molecular pathway amenable to therapeutic intervention.

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Lopez-Tobon, A., Shyti, R., Villa, C. E., Cheroni, C., Fuentes-Bravo, P., Trattaro, S., Caporale, N., Troglio, F., Tenderini, E., Mihailovich, M., Skaros, A., Gibson, W. T., Cuomo, A., Bonaldi, T., Mercurio, C., Varasi, M., Osborne, L. R., Testa, G.. 2022-10-10. GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders. https://doi.org/10.1101/2022.10.10.511434

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