Genetic modifiers of the Kvβ2-null phenotype in mice
Genetic modifiers of the Kvβ2-null phenotype in mice
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DOI：
10.1111/j.1601-183x.2004.00094.x
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发表时间：
2005-03-01
影响因子：
2.5
通讯作者：
Messing, A
中科院分区：
文献类型：
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作者：
Connor, JX;McCormack, K;Messing, A
shaker型钾（K+）通道由与细胞质β亚基相关的成孔α亚基组成。Kv β 2是哺乳动物神经系统中主要的Kv β亚基，但其在体内的功能尚不清楚。先前在我们的实验室中，Kv β 2缺失小鼠的特征是寿命缩短，冷泳引起的震颤和偶尔的癫痫发作，但Kv α亚单位运输没有明显缺陷。为了检验菌株差异是否会影响这种表型的严重程度，我们分析了不同菌株背景下的Kv β 2缺失小鼠：129/SvEv (129), C57BL/ 6J（136）和两种混合B6/129背景。我们发现菌株差异显著影响Kv β 2缺失小鼠的存活率、体重和体温调节。在这些测量中，B6 null比129 null的表型更严重；这种显著差异并不反映癫痫阈值的改变，但可能与我们在小脑Kv1.2表达中观察到的应变差异有关。为了明确Kv β 1是否是Kv β 2-null表型的遗传修饰因子，我们通过基因靶向产生Kv β 1.1缺陷小鼠，并将其与Kv β 2-null小鼠杂交。与单敲除相比，Kv β 1.1/Kv β 2双敲除显著增加了死亡率，但仍保持了Kv1.2的表面表达，这表明该α亚基的转运不需要Kv β亚基。我们的研究结果表明，129/SvEv和C57BI/6J之间的遗传差异是Kv β 2缺失小鼠缺陷严重程度的关键决定因素，Kv β 1.1是一种特异性修饰因子，尽管不是菌株依赖的修饰因子。
Shaker-type potassium (K+) channels are composed of pore-forming alpha subunits associated with cytoplasmic beta subunits. Kv beta 2 is the predominant Kv beta subunit in the mammalian nervous system, but its functions in vivo are not clear. Kv beta 2-null mice have been previously characterized in our laboratory as having reduced lifespans, cold swim-induced tremors and occasional seizures, but no apparent defect in Kv alpha-subunit trafficking. To test whether strain differences might influence the severity of this phenotype, we analyzed Kv beta 2-null mice in different strain backgrounds: 129/SvEv (129), C57BL/ 6J (136) and two mixed B6/129 backgrounds. We found that strain differences significantly affected survival, body weight and thermoregulation in Kv beta 2-null mice. B6 nulls had a more severe phenotype than 129 nulls in these measures; this dramatic difference did not reflect alterations in seizure thresholds but may relate to strain differences we observed in cerebellar Kv1.2 expression. To specifically test whether Kv beta 1 is a genetic modifier of the Kv beta 2-null phenotype, we generated Kv beta 1.1-deficient mice by gene targeting and bred them to Kv beta 2-null mice. Kv beta 1.1/Kv beta 2 double knockouts had significantly increased mortality compared with either single knockout but still maintained surface expression of Kv1.2, indicating that trafficking of this alpha subunit does not require either Kv beta subunit. Our results suggest that genetic differences between 129/SvEv and C57BI/6J are key determinants of the severity of defects seen in Kv beta 2-null mice and that Kv beta 1.1 is a specific although not strain-dependent modifier.