Cell-type specific impact of glucocorticoid receptor activation on the developing brain

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

doi:10.1101/2020.01.09.897868

Cited by 8 publications

(15 citation statements)

References 74 publications

(55 reference statements)

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“…Even here, the biological relevance is high, as increased glucocorticoid signaling during fetal development has been linked to psychiatric disorders 37,38 . Towards this, glucocorticoid treatment increases the proliferation of hiPSC-derived neural progenitor cells 39 , and impairs neuronal differentiation and maturation in hiPSC-derived neurons 15,40 and primary mouse neurons 41 . It follows from these observations that if hiPSC-derived neurons represent a fetal-like pre-trauma state, then patient-derived PBMCs represent an adult state, post-trauma and disease onset.…”

Section: Discussionmentioning

confidence: 99%

Modeling gene x environment interactions in PTSD using glucocorticoid-induced transcriptomics in human neurons

Breen

Rusielewicz

Bader

et al. 2021

Preprint

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Post-traumatic stress disorder (PTSD) results from severe trauma exposure, but the extent to which genetic and epigenetic risk factors impact individual clinical outcomes is unknown. We assessed the impact of genomic differences following glucocorticoid administration by examining the transcriptional profile of human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and live cultured peripheral blood mononuclear cells from combat veterans with PTSD (n=5) and without PTSD (n=5). This parallel examination in baseline and glucocorticoid-treated conditions resolves cell-type specific and diagnosis-dependent elements of stress response, and permits discrimination of gene expression signals associated with PTSD risk from those induced by stress. Computational analyses revealed neuron-specific glucocorticoid-response expression patterns that were enriched for transcriptomic patterns observed in clinical PTSD samples. PTSD-specific signatures, albeit underpowered, accurately stratify veterans with PTSD relative to combat-exposed controls. Overall, in vitro PTSD and glucocorticoid response signatures in blood and brain cells represent exciting new platforms with which to test the genetic and epigenetic mechanisms underlying PTSD, identify biomarkers of PTSD risk and onset, and conduct drug-screening to identify novel therapeutics to prevent or ameliorate clinical phenotypes.

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Section: Discussionmentioning

confidence: 99%

Modeling gene x environment interactions in PTSD using glucocorticoid-induced transcriptomics in human neurons

Breen

Rusielewicz

Bader

et al. 2021

Preprint

Self Cite

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“…The receptors for both natural and synthetic GCs include intracellular GC receptors (GRs) and mineralocorticoid receptors ( Seckl, 1997 ). According to a recently published preprint, the gene coding for GR, NR3C1 , is expressed in human brain organoids from day 17 to day 158 of organoid development together with the whole molecular machinery that is needed for the response to GCs ( Cruceanu et al, 2020 ). NR3C1 expression is enriched in NPCs and GR can be identified in the nuclei of the cells forming neural rosettes ( Cruceanu et al, 2020 ).…”

Section: Maternal Stress Medication and Substance Usementioning

confidence: 99%

“…According to a recently published preprint, the gene coding for GR, NR3C1 , is expressed in human brain organoids from day 17 to day 158 of organoid development together with the whole molecular machinery that is needed for the response to GCs ( Cruceanu et al, 2020 ). NR3C1 expression is enriched in NPCs and GR can be identified in the nuclei of the cells forming neural rosettes ( Cruceanu et al, 2020 ). Functionally, organoids are capable of upregulating GR-dependent gene expression upon acute exposure to dexamethasone ( Cruceanu et al, 2020 ).…”

Section: Maternal Stress Medication and Substance Usementioning

confidence: 99%

“…NR3C1 expression is enriched in NPCs and GR can be identified in the nuclei of the cells forming neural rosettes ( Cruceanu et al, 2020 ). Functionally, organoids are capable of upregulating GR-dependent gene expression upon acute exposure to dexamethasone ( Cruceanu et al, 2020 ). Moreover, single-cell transcriptomic analysis indicates differential expression of genes responsible for fate determination in the developing brain, including HES6 and PAX6 upon dexamethasone treatment ( Cruceanu et al, 2020 ).…”

Section: Maternal Stress Medication and Substance Usementioning

confidence: 99%

“…Functionally, organoids are capable of upregulating GR-dependent gene expression upon acute exposure to dexamethasone ( Cruceanu et al, 2020 ). Moreover, single-cell transcriptomic analysis indicates differential expression of genes responsible for fate determination in the developing brain, including HES6 and PAX6 upon dexamethasone treatment ( Cruceanu et al, 2020 ). Gene ontology analysis showed enrichment for cell differentiation, head development, neurogenesis, neuron differentiation, and nervous system development in both neurons and NPCs, suggesting that GC exposure in the developing brain may interfere with neuronal differentiation ( Cruceanu et al, 2020 ).…”

Section: Maternal Stress Medication and Substance Usementioning

confidence: 99%

See 2 more Smart Citations

The Effects of Environmental Adversities on Human Neocortical Neurogenesis Modeled in Brain Organoids

Sarieva

Mayer

2021

Front. Mol. Biosci.

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Over the past decades, a growing body of evidence has demonstrated the impact of prenatal environmental adversity on the development of the human embryonic and fetal brain. Prenatal environmental adversity includes infectious agents, medication, and substances of use as well as inherently maternal factors, such as diabetes and stress. These adversities may cause long-lasting effects if occurring in sensitive time windows and, therefore, have high clinical relevance. However, our knowledge of their influence on specific cellular and molecular processes of in utero brain development remains scarce. This gap of knowledge can be partially explained by the restricted experimental access to the human embryonic and fetal brain and limited recapitulation of human-specific neurodevelopmental events in model organisms. In the past years, novel 3D human stem cell-based in vitro modeling systems, so-called brain organoids, have proven their applicability for modeling early events of human brain development in health and disease. Since their emergence, brain organoids have been successfully employed to study molecular mechanisms of Zika and Herpes simplex virus-associated microcephaly, as well as more subtle events happening upon maternal alcohol and nicotine consumption. These studies converge on pathological mechanisms targeting neural stem cells. In this review, we discuss how brain organoids have recently revealed commonalities and differences in the effects of environmental adversities on human neurogenesis. We highlight both the breakthroughs in understanding the molecular consequences of environmental exposures achieved using organoids as well as the on-going challenges in the field related to variability in protocols and a lack of benchmarking, which make cross-study comparisons difficult.

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Dexamethasone promotes breast cancer stem cells in obese and not lean mice

Annett

Fox

Varešlija³

et al. 2022

Pharmacology Res & Perspec

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Obesity is highly prevalent in breast cancer patients and is associated with increased recurrence and breast cancer‐specific mortality. Glucocorticoids (GC) are used as an adjuvant in cancer treatment and are associated with promoting breast cancer metastasis through activation of stemness‐related pathways. Therefore, we utilized the synergetic allograft E0771 breast cancer model to investigate if treatment with GCs had differential effects on promoting cancer stem cells in lean and diet‐induced obese mice. Indeed, both lean mice treated with dexamethasone and obese mice with no treatment had no effect on the ex vivo colony‐forming ability, mammosphere formation, or aldehyde dehydrogenase (ALDH) bright subpopulation. However, treatment of obese mice with dexamethasone resulted in a significant increase in ex vivo colony formation, mammosphere formation, ALDH bright subpopulation, and expression of pluripotency transcription factors. GC transcriptionally regulated genes were not altered in the dexamethasone‐treated groups compared to treatment controls. In summary, these results provide initial evidence that obesity presents a higher risk of GC‐induced cancer stemness via non‐genomic GC signaling which is of potential translational significance.

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Cell-type specific impact of glucocorticoid receptor activation on the developing brain

Cited by 8 publications

References 74 publications

Modeling gene x environment interactions in PTSD using glucocorticoid-induced transcriptomics in human neurons

Modeling gene x environment interactions in PTSD using glucocorticoid-induced transcriptomics in human neurons

The Effects of Environmental Adversities on Human Neocortical Neurogenesis Modeled in Brain Organoids

Dexamethasone promotes breast cancer stem cells in obese and not lean mice

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