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

Xoel Mato-Blanco, Suel-Kee Kim, Alexandre Jourdon, Shaojie Ma, Sang-Hun Choi, Alice M. Giani, Miguel I. Paredes, Andrew T. N. Tebbenkamp, Fuchen Liu, Alvaro Duque, Flora M. Vaccarino, Nenad Sestan, Carlo Colantuoni, Pasko Rakic (), Gabriel Santpere () and Nicola Micali ()
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Xoel Mato-Blanco: Parc de Recerca Biomèdica de Barcelona (PRBB)
Suel-Kee Kim: Yale School of Medicine
Alexandre Jourdon: Yale School of Medicine
Shaojie Ma: Yale School of Medicine
Sang-Hun Choi: Yale School of Medicine
Alice M. Giani: Yale School of Medicine
Miguel I. Paredes: Yale School of Medicine
Andrew T. N. Tebbenkamp: Yale School of Medicine
Fuchen Liu: Yale School of Medicine
Alvaro Duque: Yale School of Medicine
Flora M. Vaccarino: Yale School of Medicine
Nenad Sestan: Yale School of Medicine
Carlo Colantuoni: Johns Hopkins School of Medicine
Pasko Rakic: Yale School of Medicine
Gabriel Santpere: Parc de Recerca Biomèdica de Barcelona (PRBB)
Nicola Micali: Yale School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61316-w

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