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Cruceanu, C.* ; Dony, L. ; Krontira, A.C.* ; Fischer, D.S. ; Roeh, S.* ; Di Giaimo, R.* ; Kyrousi, C.* ; Kaspar, L.* ; Knauer-Arloth, J. ; Czamara, D.* ; Martinelli, S.* ; Wehner, S.* ; Breen, M.S.* ; Koedel, M.* ; Sauer, S.* ; Sportelli, V.* ; Rex-Haffner, M.* ; Cappello, S. ; Theis, F.J. ; Binder, E.B.*

Cell-type-specific impact of glucocorticoid receptor activation on the developing brain: A cerebral organoid study.

Am. J. Psychiatry 179, 375-387 (2021)
Postprint DOI PMC
Open Access Green
OBJECTIVE: A fine-tuned balance of glucocorticoid receptor (GR) activation is essential for organ formation, with disturbances influencing many health outcomes. In utero, glucocorticoids have been linked to brain-related negative outcomes, with unclear underlying mechanisms, especially regarding cell-type-specific effects. An in vitro model of fetal human brain development, induced human pluripotent stem cell (hiPSC)-derived cerebral organoids, was used to test whether cerebral organoids are suitable for studying the impact of prenatal glucocorticoid exposure on the developing brain. METHODS: The GR was activated with the synthetic glucocorticoid dexamethasone, and the effects were mapped using single-cell transcriptomics across development. RESULTS: The GR was expressed in all cell types, with increasing expression levels through development. Not only did its activation elicit translocation to the nucleus and the expected effects on known GR-regulated pathways, but also neurons and progenitor cells showed targeted regulation of differentiation- and maturation-related transcripts. Uniquely in neurons, differentially expressed transcripts were significantly enriched for genes associated with behavior-related phenotypes and disorders. This human neuronal glucocorticoid response profile was validated across organoids from three independent hiPSC lines reprogrammed from different source tissues from both male and female donors. CONCLUSIONS: These findings suggest that excessive glucocorticoid exposure could interfere with neuronal maturation in utero, leading to increased disease susceptibility through neurodevelopmental processes at the interface of genetic susceptibility and environmental exposure. Cerebral organoids are a valuable translational resource for exploring the effects of glucocorticoids on early human brain development.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Biology ; Brain ; Child/adolescent Psychiatry ; Development ; Glucocorticoid Receptor ; Neurodevelopmental Disorders ; Pre/peri/postnatal Issues ; Stress ; Translational Research; Gene-expression; Antenatal Corticosteroids; Preterm Birth; Stress; Generation; Depression; Management; Disorders; Landscape; Exposure
ISSN (print) / ISBN 0002-953X
e-ISSN 1535-7228
Zeitschrift American Journal of Psychiatry, The
Quellenangaben Band: 179, Heft: 5, Seiten: 375-387 Artikelnummer: , Supplement: ,
Verlag American Psychiatric Association
Verlagsort 800 Maine Ave Sw, Suite 900, Washington, Dc 20024 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)