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Dony, L. ; Krontira, A.C.* ; Kaspar, L.* ; Ahmad, R.* ; Demirel, I.S.* ; Grochowicz, M.* ; Schäfer, T.* ; Begum, F.* ; Sportelli, V.* ; Raimundo, C.* ; Koedel, M.* ; Labeur, M.* ; Cappello, S.* ; Theis, F.J. ; Cruceanu, C.* ; Binder, E.B.*

Chronic exposure to glucocorticoids amplifies inhibitory neuron cell fate during human neurodevelopment in organoids.

Sci. Adv. 11:eadn8631 (2025)

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Disruptions in the tightly regulated process of human brain development have been linked to increased risk for brain and mental illnesses. While the genetic contribution to these diseases is well established, important environmental factors have been less studied at molecular and cellular levels. Here, we used single-cell and cell type-specific techniques to investigate the effect of glucocorticoid (GC) exposure, a mediator of antenatal environmental risk, on gene regulation and lineage specification in unguided human neural organoids. We characterized the transcriptional response to chronic GC exposure during neural differentiation and studied the underlying gene regulatory networks by integrating single-cell transcriptomics with chromatin accessibility data. We found lasting cell type-specific changes that included autism risk genes and several transcription factors associated with neurodevelopment. Chronic GC exposure influenced lineage specification primarily by priming the inhibitory neuron lineage through transcription factors like PBX3. We provide evidence for convergence of genetic and environmental risk factors through a common mechanism of altering lineage specification.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Antenatal Corticosteroid Treatment; Behavioral-disorders; Cerebral Organoids; Brain; Differentiation; Protein; Stress; Atlas; Risk

ISSN (print) / ISBN 2375-2548

e-ISSN 2375-2548

Journal Science Advances

Quellenangaben Volume: 11, Issue: 7, Article Number: eadn8631

Publisher American Association for the Advancement of Science (AAAS)

Publishing Place Washington, DC [u.a.]

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Computational Biology (ICB)

Grants Ministry of Bavaria within German Center for Mental Health (DZPG) Munich site
Joachim Herz Foundation
Sven and Ebba-Cristina Foundation
Jeanssons Stiftelser
StratNeuro at KI
Distinguished Investigator grant from the Brain & Behavior Research Foundation (BBRF)
Hope for Depression Research Foundation within the Depression Task Force
Federal Ministry of Education and Research
BMBF