Early developmental origins of cortical disorders modeled in human neural stem cells

Abstract

The implications of the early phases of human telencephalic development, involving neural stem cells (NSCs), in the etiology of cortical disorders remain elusive. Here, we explore the expression dynamics of cortical and neuropsychiatric disorder-associated genes in datasets generated from human NSCs across telencephalic fate transitions in vitro and in vivo. We identify risk genes expressed in brain organizers and sequential gene regulatory networks throughout corticogenesis, revealing disease-specific critical phases when NSCs may be more vulnerable to gene dysfunction and converging signaling across multiple diseases. Further, we simulate the impact of risk transcription factor (TF) depletions on neural cell trajectories traversing human corticogenesis and observe a spatiotemporal-dependent effect for each perturbation. Finally, single-cell transcriptomics of autism-affected patient-derived NSCs in vitro reveals recurrent expression alteration of TFs orchestrating brain patterning and NSC lineage commitment. This work opens perspectives to explore human brain dysfunction at early phases of development.

This study was supported in part by NIDA Merit Award DA023999 (to P.R.); NIH grant R01HG010898-01 (to G.S. and N.S.); Instituto de Salud Carlos III (CP20/00064), with co-financing by European Funds for the Miguel Servet Contract (to G.S.); grants PID2019-104700GA-I00 and PID2022-140137NB-I00 funded by /AEI/10.13039/501100011033 (to G.S.); grant 202230-30 from Fundació La Marató de TV3 (to G.S.); NIH grants HG012108, HG010898, HG012483, MH130991, U01MH116488, U01DA053628 (to N.S); NIH grant R01 MH109648 and Simons Foundation grant #632742 (to F.M.V.); MacBrain Resource Center NIH Grant MH113257 (to A.D.). Data sharing and visualization via NeMO Analytics were supported by grants R24MH114815 and R01DC019370. The authors thank the Yale Center for Genomic Analysis, Yale Animal Resource Center and Veterinary Clinical Services.