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Cited by 43Down syndrome and intellectual disability researchGenetics and Neurodevelopmental DisordersGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

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

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Block, Aaron, Ahmed, Md. Mahiuddin, Dhanasekaran, A. Ranjitha, Tong, Suhong, Gardiner, Katheleen J.·2015·Biology of Sex Differences
DOI 10.1186/s13293-015-0043-9PMC PMC4640233
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Abstract

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.

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  • In a study of expression in gene pathways of brain development in the Dp1Yey mouse model, DYRK1A was differently expressed in the hippocampi of male and female control animals aged 7 to 9 months old.

    “In a study of expression in gene pathways of brain development in the Dp1Yey mouse model, DYRK1A was differently expressed in the hippocampi of male and female control animals aged 7 to 9 months old (Block et al., 2015).”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Block et al., 2015

    The Methods (Mice; page unavailable) identify male and female Dp10 mice and controls aged 7–9 months. The Background (Modeling DS in mouse; page unavailable) reports sex differences in hippocampal protein levels among controls, but the passages found do not identify DYRK1A as one of those proteins. The specific DYRK1A finding is therefore unsupported by our copy. (LLM, conf=0.88)

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Authors
Block, A., Ahmed, M. M., Dhanasekaran, A. R., Tong, S., & Gardiner, K. J.
Affiliations
  • Colorado School of Public Health (US)
  • University of Colorado Anschutz (US)
Corresponding author
Gardiner, Katheleen J.
ORCID
Tong, Suhong
Venue
Biology of Sex Differences
Publisher
Springer Science and Business Media LLC
Published
2015-11-09
Volume
6
Issue
1
Pages
24-24
ISSN
2042-6410 (ISSN-L)
DOI
10.1186/s13293-015-0043-9
PMC
PMC4640233
OpenAlex
W2179689712
Cited by
43
References
89
Citations by year
2025: 2 · 2024: 2 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 6 · 2016: 3
FWCI
5.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Biology of Sex Differences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institute of Child Health and Human Development (HD071585)
  • The Linda Crnic Institute for Down Syndrome
  • Fondation Jérôme Lejeune
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords
sex differences, Down syndrome, intellectual disability, protein expression, hippocampus, cerebellum, cortex, learning and memory, synaptic plasticity, MAPK signaling, mTOR signaling, apoptosis, ionotropic glutamate receptors, immediate early genes

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