Strain-dependent influences on the hypothalamo-pituitary-adrenal axis profoundly affect the 7B2 and PC2 null phenotypes
Strain-dependent influences on the hypothalamo-pituitary-adrenal axis profoundly affect the 7B2 and PC2 null phenotypes
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DOI：
10.1210/en.2004-1289
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发表时间：
2005-08-01
期刊：
影响因子：
4.8
通讯作者：
Lindberg, I
中科院分区：
文献类型：
--
作者：
Peinado, JR;Laurent, V;Lindberg, I
先前已经建立了两种无效小鼠模型来研究激素原转化酶（PC 2）及其辅助蛋白7 B2的作用;出乎意料的是，这两种无效小鼠的表型差异很大，7 B2在5周时死亡，而PC 2无效小鼠则没有。这两个模型的遗传背景不同，7 B2无效在129/SvEv（129）背景中，而PC 2无效在混合C57 BL/N6：129/SvEv（B6：129）背景中。由于背景可以大大有助于表型，我们在这里检查了应变的影响下丘脑-垂体-肾上腺（HPA）轴和葡萄糖水平的野生型，7 B2无效，和PC 2无效小鼠。野生型B6和129小鼠的基础皮质酮和葡萄糖水平不同。当7 B2空细胞转移到B6背景下时，它们存活下来，并显示循环皮质酮大大降低，血糖水平升高，这很可能是由于B6品系对ACTH刺激的肾上腺抵抗力相对较高。循环ACTH水平在B6 7 B2 null中比野生型增加，但没有达到129 7 B2 null的水平。相反，当混合品系PC 2无效小鼠在N6代与129背景小鼠交配时，它们开始表现出129 7 B2无效小鼠的库欣样表型特征，并在6周龄前死亡。综上所述，这些结果表明背景效应是关键的，因为它们增加了7 B2和PC 2无效之间的表型差异，并在129个无效中存在的ACTH分泌过多综合征中起着生死攸关的作用。
Two null mouse models have previously been created to study the role of the prohormone convertase (PC2) and its helper protein 7B2; unexpectedly, the phenotypes of these two nulls differ profoundly, with the 7B2 but not the PC2 null dying at 5 wk. The genetic backgrounds of these two models differ, with the 7B2 null in a 129/SvEv ( 129) background and the PC2 null in a mixed C57BL/N6: 129/SvEv (B6: 129) background. Because background can contribute greatly to phenotype, we have here examined strain influence on the hypothalamo-pituitary-adrenal (HPA) axis and glucose levels in wild-type, 7B2 null, and PC2 null mice. Wild-type B6 and 129 mice differed in basal corticosterone and glucose levels. When 7B2 nulls were transferred onto the B6 background, they survived and showed greatly decreased circulating corticosterone and increased blood glucose levels, most likely due to the comparatively higher adrenal resistance of the B6 strain to ACTH stimulation. Circulating ACTH levels were increased over wild-type in the B6 7B2 null but did not reach levels as high as the 129 7B2 null. Conversely, when the mixed-strain PC2 nulls were bred into the 129 background at the N6 generation, they began to exhibit the Cushing's-like phenotype characteristic of 129 7B2 null mice and died before 6 wk of age. Taken together, these results indicate that background effects are critical because they increase the phenotypic differences between the 7B2 and PC2 nulls and play a life-or-death role in the ACTH hypersecretion syndrome present in both 129 nulls.