Genetic control of sensitivity to hippocampal cell death induced by kainic acid: A quantitative trait loci analysis
Genetic control of sensitivity to hippocampal cell death induced by kainic acid: A quantitative trait loci analysis
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DOI：
10.1002/cne.20245
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发表时间：
2004-09-06
影响因子：
2.5
通讯作者：
Santos, JB
中科院分区：
文献类型：
--
作者：
Schauwecker, PE;Williams, RW;Santos, JB
宿主遗传因素可能导致个体对乙酰胆碱诱导的兴奋性毒性神经元损伤易感性的差异。类似地，近交系小鼠对海人酸（KA）诱导细胞死亡模型的易感性不同，但导致差异的基因尚不清楚。在这里，我们定义的遗传模式的易感性KA诱导的神经退行性病变的海马通过评估331回交（N2）后代的两个近交系小鼠品系，C57 BL/6和FVB/N，以前显示的电阻和敏感性KA诱导的细胞死亡，分别。表型分析结果表明，这两个菌株之间的易感性的差异是由一个单一的显性基因。因此，我们使用近交系C57 BL/6和FVB/N株系之间的N2回交，在全基因组范围内搜索数量性状位点（QTL），这些位点是含有影响易感性大小的基因的染色体位点。在N2子代中的全基因组间隔作图鉴定了远端染色体（Chr）18上的基因座，其峰值LOD评分为4.9，位于D18 Mit 186和D18 Mit 4之间，在该模型中具有最强和最显著的影响。在第15个（D15 Mit 174-D15 Mit 156）和第4个（D4 Mit 264-D4 Mit 91）染色体上检测到影响较小的QTL，LOD值分别为3.02和2.46。3个显著的QTL（Chrs 4、15、18）共同解释了两个性别组合的近25%的性状方差。KA诱导的细胞死亡的敏感性降低，观察到在同源株，其中高度敏感的FVB/N株携带推定的抗性等位基因从C57 BL/6菌株的Chr 18。(C)2004 Wiley-Liss，Inc.
Host genetic factors are likely to contribute to differences in individual susceptibility to seizure-induced excitotoxic neuronal damage. Similarly, inbred strains of mice differ in their susceptibility to the kainic acid (KA) model of seizure-induced cell death, but the genes responsible for the differences are not known. Here, we define the inheritance patterns of susceptibility to KA-induced neurodegeneration in the hippocampus by assessing 331 backcross (N2) progeny of two inbred mouse strains, C57BL/6 and FVB/N, previously shown to display resistance and sensitivity to KA-induced cell death, respectively. Results of phenotypic analysis suggest that the difference in susceptibility between these two strains is conferred by a single dominant gene. Therefore, we used an N2 back-cross between the inbred C57BL/6 and FVB/N strains for a genome-wide search for quantitative trait loci (QTLs), which are chromosomal sites containing genes influencing the magnitude of susceptibility. Genome-wide interval mapping in N2 progeny identified a locus on distal chromosome (Chr) 18 with a peak LOD score of 4.9 localized between D18Mit186 and D18Mit4 as having the strongest and most significant effect in this model. QTLs of minor effect were detected on Chr 15 (D15Mit174-D15Mit156) and Chr 4 (D4Mit264-D4Mit91), with peak LOD scores of 3.02 and 2.46, respectively. The three significant QTLs (Chrs 4, 15, 18) together account for nearly 25% of the trait variance for both genders combined. Reduced KA-induced cell death susceptibility was observed in a congenic strain in which the highly susceptible FVB/N strain carried putative resistance alleles from the C57BL/6 strain on Chr 18. (C) 2004 Wiley-Liss, Inc.