Sex differences in the molecular signature of the developing mouse hippocampus

Joseph L. Bundy,Richard S. Nowakowski,Cynthia Vied

doi:10.1186/s12864-017-3608-7

Abstract

BackgroundA variety of neurological disorders, including Alzheimer’s disease, Parkinson’s disease, major depressive disorder, dyslexia and autism, are differentially prevalent between females and males. To better understand the possible molecular basis for the sex-biased nature of neurological disorders, we used a developmental series of female and male mice at 1, 2, and 4 months of age to assess both mRNA and protein in the hippocampus with RNA-sequencing and mass-spectrometry, respectively.ResultsThe transcriptomic analysis identifies 2699 genes that are differentially expressed between animals of different ages. The bulk of these differentially expressed genes are changed in both sexes at one or more ages, but a total of 198 transcripts are differentially expressed between females and males at one or more ages. The number of transcripts that are differentially expressed between females and males is greater in adult animals than in younger animals. Additionally, we identify 69 transcripts that show complex and sex-specific patterns of temporal regulation through postnatal development, 8 of which are heat-shock proteins. We also find a modest correlation between levels of mRNA and protein in the mouse hippocampus (Rho = 0.53).ConclusionThis study adds to the substantial body of evidence for transcriptomic regulation in the hippocampus during postnatal development. Additionally, this analysis reveals sex differences in the transcriptome of the developing mouse hippocampus, and further clarifies the need to include both female and male mice in longitudinal studies involving molecular changes in the hippocampus.

Highlights

A variety of neurological disorders, including Alzheimer’s disease, Parkinson’s disease, major depressive disorder, dyslexia and autism, are differentially prevalent between females and males
Within clusters of female and male samples, mice of different ages and both sexes are further segregated by contributions from both PC2 and PC3, confirming that the Temporal dynamics of the transcriptome in postnatal development To identify the individual transcripts which 1) are differentially expressed at one or more ages, 2) are differentially expressed between the sexes, and 3) are differentially expressed over time differently between the sexes, we conducted a series of differential expression analyses using DESeq2
This study shows that layered on top of the broad changes in gene expression that take place in postnatal development, the transcriptional signatures of the developing female and male hippocampus are distinct

Summary

Introduction

A variety of neurological disorders, including Alzheimer’s disease, Parkinson’s disease, major depressive disorder, dyslexia and autism, are differentially prevalent between females and males. Transcriptional regulation of neural development has previously been explored using mouse models with high throughput technologies such as microarrays and RNAsequencing (RNA-seq) [2,3,4,5,6] These investigations have focused on a variety of brain regions, including the cerebral cortex [2, 3], hippocampus [6], and cerebellum [4]. Additional sex differences in gene expression and brain morphology manifest as a result of the gonadal release of sex hormones both in utero and during postnatal sexual development [9,10,11]. Our detailed investigation of sex differences in transcript expression in inbred mouse strains showed that molecular sex differences are

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