Cell-Type-Specific Impact of Glucocorticoid Receptor Activation on the Developing Brain: A Cerebral Organoid Study

Cruceanu, Cristiana; Dony, Leander; Krontira, Anthi C.; Fischer, David; Roeh, Simone; Giaimo, Rossella Di; Kyrousi, Christina; Kaspar, Lea; Arloth, Janine; Gerstner, Nathalie; Martinelli, Silvia; Wehner, Stefanie; Breen, Michael S.; Koedel, Maik; Sauer, Susann; Sportelli, Vincenza; Rex‐Haffner, Monika; Cappello, Silvia; Theis, Fabian J.; Binder, Elisabeth B.

doi:10.1176/appi.ajp.2021.21010095

Cited by 38 publications

(43 citation statements)

References 88 publications

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“…We also found that from the development of the iPSC to iPS-Mg, the expression of NR3C1 increased. Previously Lieberman et al 47 (2017) demonstrated that GR mRNA expression levels increased during the differentiation of iPSC-derived neural cells; GR mRNA has also been shown to be increased in human iPS derived cerebral organoids 71 (Cruceanu et al 2020). We also report that GR activation led to an increase in FKBP5, FKBP5-201 and FKBP5-204.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid receptor activation during human microglial differentiation leads to genomic instability and senescence

Wei

Arber

Wray

et al. 2022

Preprint

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Early life stress, prenatal exposure to glucocorticoids (GCs), confers a higher risk of psychiatric and neurodevelopmental disorders in children. Increasingly, the importance of microglia in these disorders has been recognised. Studies on GCs exposure during microglial development have been limited, and there are few, if any, human studies. We established an in vitro model of ELS by continuous pre-expoure of human iPS-microglia to GCs during primitive haematopoiesis (the critical stage of iPS-microglial differentiation) and then examined how this exposure affected the microglial phenotype as they differentiated and matured to microglia. The iPS-microglia predominately expressed glucocorticoid receptors over mineralocorticoid receptors, and the GR-α splice variant. Chronic GCs exposure during primitive haematopoiesis was able to recapitulate in vivo ELS effects. Thus pre-exposure to prolonged GCs resulted in increased type I interferon signalling, the presence of Cyclic GMP-AMP synthase-positive (cGAS) micronuclei, and cellular senescence in the matured iPS-microglia. The findings from this in vitro ELS model have ramifications for the responses of microglia in the pathogenesis of GC-mediated ELS-associated disorders such as schizophrenia, attention-deficit hyperactivity disorder and autistic spectrum disorder.

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Section: Discussionmentioning

confidence: 99%

Glucocorticoid receptor activation during human microglial differentiation leads to genomic instability and senescence

Wei

Arber

Wray

et al. 2022

Preprint

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“…Glucocorticoid receptor and MR activation may affect neuronal development, 99 as exemplified in CA2 pyramidal cells for MR 49 and the DG granule cells for GR 100 . This may be linked to corresponding downstream regulatory pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Our data also confirm the predominant role of CA2 specific AVPR1B receptors in stress-related signaling, in conjunction with MR (Figure 6A). Glucocorticoid receptor and MR activation may affect neuronal development, 99 as exemplified in CA2 pyramidal cells for MR 49 and the DG granule cells for GR. 100 This may be linked to corresponding downstream regulatory pathways.…”

Section: Discussionmentioning

confidence: 99%

Cell type specificity of glucocorticoid signaling in the adult mouse hippocampus

Viho

Buurstede

Berkhout

et al. 2021

J Neuroendocrinology

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Glucocorticoid stress hormones are powerful modulators of brain function and can affect mood and cognitive processes. The hippocampus is a prominent glucocorticoid target and expresses both the glucocorticoid receptor (GR: Nr3c1) and the mineralocorticoid receptor (MR: Nr3c2). These nuclear steroid receptors act as ligand‐dependent transcription factors. Transcriptional effects of glucocorticoids have often been deduced from bulk mRNA measurements or spatially informed individual gene expression. However, only sparse data exists allowing insights on glucocorticoid‐driven gene transcription at the cell type level. Here, we used publicly available single‐cell RNA sequencing data to assess the cell‐type specificity of GR and MR signaling in the adult mouse hippocampus. The data confirmed that Nr3c1 and Nr3c2 expression differs across neuronal and non‐neuronal cell populations. We analyzed co‐expression with sex hormones receptors, transcriptional coregulators, and receptors for neurotransmitters and neuropeptides. Our results provide insights in the cellular basis of previous bulk mRNA results and allow the formulation of more defined hypotheses on the effects of glucocorticoids on hippocampal function.

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“…Two induced pluripotent stem cell (iPSC) lines were generated as previously described 82 from 2 distinct healthy donors. Cells were quality controlled by immunofluorescence for OCT4, NANOG, and SOX.…”

Section: Methods Related To Supplemental Figurementioning

confidence: 99%

Assessment of glucocorticoid-induced enhancer activity of eSNP regions using STARR-seq reveals novel molecular mechanisms in psychiatric disorders

Penner-Goeke

Bothe

Kappelmann

et al. 2022

Preprint

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Exposure to stressful events increases risk for psychiatric disorders. Mechanistic insight into genetic factors moderating the impact of stress can increase our understanding of disease processes. Here, we test 3662 SNPs from preselected expression quantitative trait loci in massively parallel reporter assays to identify genetic variants that modulate the activity of regulatory elements sensitive to glucocorticoids, important mediators of the stress response. Of the tested SNP sequences, 547 were located in glucocorticoid-responsive regulatory elements of which 233 showed allele-dependent activity. Transcripts regulated by these variants were enriched for those differentially expressed in psychiatric disorders in postmortem brain. Phenome-wide Mendelian randomization analysis in 4,439 phenotypes revealed potentially causal associations specifically in neuro-behavioral traits, including psychiatric disorders. Finally, functional gene scores derived from these variants were significantly associated with differences in physiological stress measures, suggesting that these may alter disease risk by moderating the individual set point of the stress response.

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Cell-Type-Specific Impact of Glucocorticoid Receptor Activation on the Developing Brain: A Cerebral Organoid Study

Cited by 38 publications

References 88 publications

Glucocorticoid receptor activation during human microglial differentiation leads to genomic instability and senescence

Glucocorticoid receptor activation during human microglial differentiation leads to genomic instability and senescence

Cell type specificity of glucocorticoid signaling in the adult mouse hippocampus

Assessment of glucocorticoid-induced enhancer activity of eSNP regions using STARR-seq reveals novel molecular mechanisms in psychiatric disorders

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