The Relative Contribution of Proximal 5′ Flanking Sequence and Microsatellite Variation on Brain Vasopressin 1a Receptor (Avpr1a) Gene Expression and Behavior
The Relative Contribution of Proximal 5′ Flanking Sequence and Microsatellite Variation on Brain Vasopressin 1a Receptor (Avpr1a) Gene Expression and Behavior
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DOI：
10.1371/journal.pgen.1003729
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发表时间：
2013-08-01
期刊：
影响因子：
4.5
通讯作者：
Young, Larry J.
中科院分区：
文献类型：
--
作者：
Donaldson, Zoe R.;Young, Larry J.
某些基因在物种内部和物种之间的表达模式中表现出显着的多样性。一个这样的基因是加压素受体1a基因（Avpr1a），它在神经表达模式上表现出惊人的差异，这些差异负责介导加压素介导的社会行为的差异。导致这些显著表达差异的基因组机制还不清楚。先前的研究表明，田鼠Avpr1a基因的近端5'侧翼区和该区域内的多态性微卫星元件与V1a受体（V1aR）分布和行为的变化相关，但两者都没有因果联系。在小鼠中使用同源重组，我们揭示了近端5'侧翼序列对V1aR分布的物种差异的适度贡献，并证实V1aR分布的变化影响强迫游泳测试中的压力应对。我们还证明，田鼠Avpr 1a微卫星结构有助于Avpr 1a在杏仁核、丘脑和海马体中的表达，反映了在田鼠中央V1 aR模式中观察到的种间和种内差异的一个子集。这是第一个直接的证据表明，多态性微卫星元件附近的行为相关的基因可以有助于大脑基因表达谱的多样性，提供了一种机制，在个人和物种水平上产生的行为多样性。然而，我们的研究结果表明，物种特异性表达模式的许多功能是由基因的直接5'侧翼区以外的元件介导的。
Certain genes exhibit notable diversity in their expression patterns both within and between species. One such gene is the vasopressin receptor 1a gene (Avpr1a), which exhibits striking differences in neural expression patterns that are responsible for mediating differences in vasopressin-mediated social behaviors. The genomic mechanisms that contribute to these remarkable differences in expression are not well understood. Previous work has suggested that both the proximal 5' flanking region and a polymorphic microsatellite element within that region of the vole Avpr1a gene are associated with variation in V1a receptor (V1aR) distribution and behavior, but neither has been causally linked. Using homologous recombination in mice, we reveal the modest contribution of proximal 5' flanking sequences to species differences in V1aR distribution, and confirm that variation in V1aR distribution impacts stress-coping in the forced swim test. We also demonstrate that the vole Avpr1a microsatellite structure contributes to Avpr1a expression in the amygdala, thalamus, and hippocampus, mirroring a subset of the inter-and intra-species differences observed in central V1aR patterns in voles. This is the first direct evidence that polymorphic microsatellite elements near behaviorally relevant genes can contribute to diversity in brain gene expression profiles, providing a mechanism for generating behavioral diversity both at the individual and species level. However, our results suggest that many features of species-specific expression patterns are mediated by elements outside of the immediate 5' flanking region of the gene.