Sex differences in protein expression in the mouse brain and their perturbations in a model of Down syndrome.
Sex differences in protein expression in the mouse brain and their perturbations in a model of Down syndrome.
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DOI：
10.1186/s13293-015-0043-9
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发表时间：
2015
影响因子：
7.9
通讯作者：
Gardiner KJ
中科院分区：
文献类型：
--
作者：
Block A;Ahmed MM;Dhanasekaran AR;Tong S;Gardiner KJ
虽然哺乳动物大脑的结构和功能存在许多性别差异，但这些差异的分子相关性并不广为人知。同样未知的是，蛋白质水平上的性别差异如何受到导致智力残疾（ID）的突变的干扰。唐氏综合征（DS）是ID最常见的遗传原因，是由于人类21号染色体（Hsa 21）的三体性和由此产生的Hsa 21编码基因表达增加。DS的Dp（10）1 Yey小鼠模型（Dp 10）是39个Hsa 21蛋白编码基因的直向同源物的三体，这些基因定位于小鼠10号染色体（Mmu 10），包括4个功能特性具有已知性别差异的基因。这些基因如何导致DS认知表型尚不清楚。使用反相蛋白质阵列，在雌性和雄性对照及其三体Dp 10同窝仔的海马、小脑和皮质中测量~100种蛋白质/蛋白质修饰的水平。蛋白质的选择是因为它们在学习/记忆和突触可塑性中的已知作用，包括MAPK、MTOR和凋亡途径的组分、立即早期基因和离子型谷氨酸受体的亚基。使用三水平混合效应模型和Benjamini-Hochberg校正进行多重检验，比较基因型、性别和脑区之间的蛋白质水平。在对照小鼠中，雌性和雄性之间至少有一个脑区中约一半的蛋白质水平存在显著差异;仅在海马体中，雌性中40%的蛋白质水平显著较高。三体的Mmu 10段差异影响女性和男性的配置文件，扰动蛋白质水平最在小脑的女性Dp 10和最在海马的男性Dp 10。皮质受性别和基因型的影响最小。不同的途径和过程涉及性别和基因型差异。对照组小鼠在参与学习/记忆的蛋白质水平方面存在广泛的性别差异，这说明了正常神经过程中性别差异的分子复杂性。Dp 10中的性别特异性异常表明DS中可能存在性别特异性表型特征，并加强了使用雌性和雄性小鼠的必要性，特别是在药物反应的临床前评价中。本文的在线版本（doi：10.1186/s13293-015-0043-9）包含补充材料，可供授权用户使用。
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. 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. 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. 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. The online version of this article (doi:10.1186/s13293-015-0043-9) contains supplementary material, which is available to authorized users.