Sex differences in protein expression in the mouse brain and their perturbations in a model of Down syndrome

Biology of Sex Differences

Aaron Block³  Md. Mahiuddin Ahmed³  A. Ranjitha Dhanasekaran³  Suhong Tong²  Katheleen J. Gardiner¹ 

[1] Human Medical Genetics and Genomics, and Neuroscience Programs, University of Colorado Denver School of Medicine, 12700 E 19th Avenue, Mail Stop 8608, Aurora 80045, CO, USA

[2] Colorado School of Public Health, Aurora, USA

[3] Department of Pediatrics, Linda Crnic Institute for Down Syndrome, Aurora, USA

关键词: Intellectual disability;    Cerebellum;    S100B;    TRPM2;    Learning and memory deficits;    Hippocampus;    Mouse chromosome 10;    Dp(10)1Yey;    Trisomy 21;   

Others  :  1232377
DOI  :  10.1186/s13293-015-0043-9

 received in 2015-07-24, accepted in 2015-11-01,  发布年份 2015

【 摘 要 】

Background

While many sex differences in structure and function of the mammalian brain have been described, the molecular correlates of these differences are not broadly known. Also unknown is how sex differences at the protein level are perturbed by mutations that lead to intellectual disability (ID). Down syndrome (DS) is the most common genetic cause of ID and is due to trisomy of human chromosome 21 (Hsa21) and the resulting increased expression of Hsa21-encoded genes. The Dp(10)1Yey mouse model (Dp10) of DS is trisomic for orthologs of 39 Hsa21 protein-coding genes that map to mouse chromosome 10 (Mmu10), including four genes with known sex differences in functional properties. How these genes contribute to the DS cognitive phenotype is not known.

Methods

Using reverse phase protein arrays, levels of ~100 proteins/protein modifications were measured in the hippocampus, cerebellum, and cortex of female and male controls and their trisomic Dp10 littermates. Proteins were chosen for their known roles in learning/memory and synaptic plasticity and include components of the MAPK, MTOR, and apoptosis pathways, immediate early genes, and subunits of ionotropic glutamate receptors. Protein levels were compared between genotypes, sexes, and brain regions using a three-level mixed effects model and the Benjamini-Hochberg correction for multiple testing.

Results

In control mice, levels of approximately one half of the proteins differ significantly between females and males in at least one brain region; in the hippocampus alone, levels of 40 % of the proteins are significantly higher in females. Trisomy of the Mmu10 segment differentially affects female and male profiles, perturbing protein levels most in the cerebellum of female Dp10 and most in the hippocampus of male Dp10. Cortex is minimally affected by sex and genotype. Diverse pathways and processes are implicated in both sex and genotype differences.

Conclusions

The extensive sex differences in control mice in levels of proteins involved in learning/memory illustrate the molecular complexity underlying sex differences in normal neurological processes. The sex-specific abnormalities in the Dp10 suggest the possibility of sex-specific phenotypic features in DS and reinforce the need to use female as well as male mice, in particular in preclinical evaluations of drug responses.

【 授权许可】

   
2015 Block et al.

【 图 表 】

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