A comparison of the sexually dimorphic dexamethasone transcriptome in mouse cerebral cortical and hypothalamic embryonic neural stem cells

Abstract

Fetal exposure to synthetic glucocorticoids reprograms distinct neural circuits in the developing brain, often in a sex-specific manner, via mechanisms that remain poorly understood. To reveal whether such reprogramming is associated with select molecular signatures, we characterized the transcriptome of primary, embryonic mouse cerebral cortical and hypothalamic neural progenitor/stem cells derived from individual male and female embryos exposed to the synthetic glucocorticoid, dexamethasone. Gene expression profiling by RNA-Seq identified differential expression of common and unique genes based upon brain region, sex, and/or dexamethasone exposure. These gene expression datasets provide a unique resource that will inform future studies examining the molecular mechanisms responsible for region- and sex-specific reprogramming of the fetal brain brought about by in utero exposure to excess glucocorticoids.

Expression and glucocorticoid-dependent regulation of the stress-inducible protein DRR1 in the mouse adult brain

“…The lateral septum has also a key role in integrating information from affective brain regions, especially from hippocampus and hypothalamus among others (Sheehan et al 2004). Also, the hypothalamus, where DRR1 expression is strongly induced by dexamethasone in hypothalamic neural-progenitor/stem cells derived from mouse embryos (Frahm et al 2016, 2017), integrates inputs from many central and peripheral sources to maintain homeostasis of different organ systems and whole body metabolism (Denton et al 1996). …”

A powerful and flexible tool for rapid and accurate differential expression and alternative splicing analysis of RNA-seq data for biologists

“…To illustrate the utility of the 3D RNA-seq App in analysing multi-factor RNA-seq data from animals, we re-analysed RNA-seq data which studied the effects of dexamethasone treatment on cortical and hypothalamic neural progenitor/stem cells (NPSCs) from male and female mice (Frahm et al, 2018) The RNA-seq data consisted of male and female cortex and hypothalmus cell cultures treated or untreated with dexamethasone, each with three biological replicates (24 samples in total). The study identified differentially expressed genes common and unique to brain region, gender and dexamethasone treatment (Frahm et al, 2018). The same dataset has also been used to demonstrate the improved resolution of differentially expressed genes using Sleuth for transcript-level differential analysis and aggregation of transcript level pvalues to give gene-level p-values (Yi et al, 2018).…”

“…The same dataset has also been used to demonstrate the improved resolution of differentially expressed genes using Sleuth for transcript-level differential analysis and aggregation of transcript level pvalues to give gene-level p-values (Yi et al, 2018). Using this data, we performed two differential expression comparisons between: 1) the Sleuth/aggregated p-values method (Pimentel et al, 2017;Yi et al, 2018) and 3D RNA-seq and 2) the results of the differential analysis in Frahm et al, (2018) and those generated by 3D RNA-seq expression results.…”

“…The second comparison exploited the flexibility of 3D RNA-seq to analyse the effects of multiple factors and detect sex-specific and brain region-specific DE and DAS genes and transcripts in the mouse data. In the original study, the effects of dexamethasone treatment on differential gene expression in NPSCs from different brain (cortical and hypothalamic) and sexes (male and female), were examined (Frahm et al, 2018). We therefore set up contrast were AS regulated only.…”

“…The relative differences between brain regions at the DE gene level was described by Frahm et al, (2018). We also compared the DE genes from the 3D pipeline to those of Frahm et al, (2018) which used a p-value cut-off of < 0.05 (note: p-values were not adjusted and no 2 cut-off was applied).…”