High-resolution genetic mapping of mammalian motor activity levels in mice
High-resolution genetic mapping of mammalian motor activity levels in mice
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DOI：
10.1111/j.1601-183x.2008.00435.x
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发表时间：
2009-02-01
影响因子：
2.5
通讯作者：
de Graan, P. N. E.
中科院分区：
文献类型：
--
作者：
Kas, M. J. H.;Malsen, J. G. de Mooij-van;de Graan, P. N. E.
运动活动水平的产生受到严格的神经控制，以执行基本行为，例如走向食物或进行社交互动。为了确定运动活动水平背后的新神经生物学机制，我们使用自动化的家用笼行为登记研究了一组来自高运动活动水平（C57BL/6J 品系）或低运动活动水平（A/J 品系）小鼠的染色体替换（CS）品系。在这项研究中，我们将基线运动水平（水平移动距离）的表达基因映射到小鼠 1 号染色体。该性状的进一步基因映射揭示了 8.3 Mb 数量性状位点 (QTL) 间隔。该基因座与该染色体上与旷场焦虑相关运动行为的 QTL 区间不同。通过数据挖掘，2445只遗传异质小鼠的现有表型和基因型数据集（http://gscan.well.ox.ac.uk），我们确认了与79 970 253 bp处的峰值标记的连锁，并将QTL细化至包含单个基因（A830043J08Rik）的312 kb区间。序列分析显示Riken基因的3'非翻译区存在核苷酸缺失。来自 CS 品系 1 的不一致 F-2 个体大脑中的全基因组微阵列基因表达谱显示，低活性 F-2 个体中 Epha4 显着上调。 Epha4 遗传标记的包含证实了该基因位于 QTL 区间之外。 Epha4 和 A830043J08Rik 均在脑运动回路中表达，与 Epha4 突变体类似，我们发现运动神经元数量减少与 A/J 染色体 1 之间存在联系。我们的研究结果提供了一个新的 QTL 和潜在的运动回路发育和体力活动水平表达的下游靶标。
The generation of motor activity levels is under tight neural control to execute essential behaviors, such as movement toward food or for social interaction. To identify novel neurobiological mechanisms underlying motor activity levels, we studied a panel of chromosome substitution (CS) strains derived from mice with high (C57BL/6J strain) or low motor activity levels (A/J strain) using automated home cage behavioral registration. In this study, we genetically mapped the expression of baseline motor activity levels (horizontal distance moved) to mouse chromosome 1. Further genetic mapping of this trait revealed an 8.3-Mb quantitative trait locus (QTL) interval. This locus is distinct from the QTL interval for open-field anxiety-related motor behavior on this chromosome. By data mining, an existing phenotypic and genotypic data set of 2445 genetically heterogeneous mice (http://gscan.well.ox.ac.uk), we confirmed linkage to the peak marker at 79 970 253 bp and refined the QTL to a 312-kb interval containing a single gene (A830043J08Rik). Sequence analysis showed a nucleotide deletion in the 3' untranslated region of the Riken gene. Genome-wide microarray gene expression profiling in brains of discordant F-2 individuals from CS strain 1 showed a significant upregulation of Epha4 in low-active F-2 individuals. Inclusion of a genetic marker for Epha4 confirmed that this gene is located outside of the QTL interval. Both Epha4 and A830043J08Rik are expressed in brain motor circuits, and similar to Epha4 mutants, we found linkage between reduced motor neurons number and A/J chromosome 1. Our findings provide a novel QTL and a potential downstream target underlying motor circuitry development and the expression of physical activity levels.