Sex and oestrogen receptor β have modest effects on gene expression in the mouse brain posterior cortex

Abstract

Introduction Sex differences in brain cortical function affect cognition, behaviour and susceptibility to neural diseases, but the molecular basis of sexual dimorphism in cortical function is still largely unknown. Oestrogen and oestrogen receptors (ERs), specifically ERβ, the most abundant ER in the cortex, may play a role in determining sex differences in gene expression, which could underlie functional sex differences. However, further investigation is needed to address brain region specificity of the effects of sex and ERβ on gene expression. The goal of this study was to investigate sex differences in gene expression in the mouse posterior cortex, where sex differences in transcription have never been examined, and to determine how genetic ablation of ERβ affects transcription. Methods In this study, we performed unbiased transcriptomics on RNA from the posterior cortex of adult wild‐type and ERβ knockout mice (n = 4/sex/genotype). We used unbiased clustering to analyse whole‐transcriptome changes between the groups. We also performed differential expression analysis on the data using DESeq2 to identify specific changes in gene expression. Results We found only 27 significantly differentially expressed genes (DEGs) in wild‐type (WT) males vs females, of which 17 were autosomal genes. Interestingly, in ERβKO males vs females all the autosomal DEGs were lost. Gene Ontology analysis of the subset of DEGs with sex differences only in the WT cortex revealed a significant enrichment of genes annotated with the function ‘cation channel activity’. Moreover, within each sex we found only a few DEGs in ERβKO vs WT mice (8 and 5 in males and females, respectively). Conclusions Overall, our results suggest that in the adult mouse posterior cortex there are surprisingly few sex differences in gene expression, and those that exist are mainly related to cation channel activity. Additionally, they indicate that brain region‐specific functional effects of ERβ may be largely post‐transcriptional.

Astrocyte-Derived Thrombospondin Induces Cortical Synaptogenesis in a Sex-Specific Manner

“…6 ). A number of groups have previously investigated sex differences in aromatase expression throughout the CNS ( Bender et al, 2017 ; Fels et al, 2021 ; Tabatadze et al, 2014 ). Though the studies varied in terms of age as well as methodology (mRNA vs protein), a common conclusion is that sex differences do exist in some brain regions but not others.…”