Cell-type specific impact of glucocorticoid receptor activation on the developing brain
Cruceanu, C.; Dony, L.; Kontira, A. C.; Fischer, D. S.; Roeh, S.; Di Giaimo, R.; Kyrousi, C.; Arloth, J.; Czamara, D.; Martinelli, S.; Wehner, S.; Breen, M. S.; Koedel, M.; Sauer, S.; Rex-Haffner, M.; Cappello, S.; Theis, F. J.; Binder, E.
Show abstract
A fine-tuned balance of glucocorticoid receptor (GR) activation is essential for organ formation, with disturbances influencing health outcomes. Excess GR-activation in utero has been linked to brain-related negative outcomes, with unclear underlying mechanisms, especially regarding cell-type specific effects. To address this, we used an in vitro model of fetal human brain, induced pluripotent-stem-cell-derived cerebral organoids, and mapped GR-activation effects using single-cell transcriptomics across development. Interestingly, neurons showed targeted regulation of differentiation- and maturation-related transcripts, suggesting a delay of these processes upon GR-activation. Uniquely in neurons, differentially-expressed transcripts were significantly enriched for genes associated with behavior-related phenotypes and disorders. This suggests that aberrant GR-activation could impact proper neuronal maturation, leading to increased disease susceptibility, through neurodevelopmental processes at the interface of genetic susceptibility and environmental exposure.
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