Class 2 IGF-1 isoforms are dispensable for viability, growth and maintenance of IGF-1 serum levels
Class 2 IGF-1 isoforms are dispensable for viability, growth and maintenance of IGF-1 serum levels
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DOI：
10.1016/j.ghir.2010.03.002
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发表时间：
2010-06-01
影响因子：
1.4
通讯作者：
Rosenthal, N.
中科院分区：
文献类型：
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作者：
Temmerman, L.;Slonimsky, E.;Rosenthal, N.
胰岛素样生长因子1（IGF-1）是一种多效因子，参与生长、细胞存活和细胞分化。它通过内分泌、旁分泌或自分泌机制发挥其功能。循环中的IGF-1对于正常的胎儿和出生后的生长是必不可少的，尽管已发表的IGF-1缺失动物的表型仅部分外显，可能是由于混合的遗传背景。IGF-1作用的分子解剖由于存在至少九种不同的IGF-1同种型而变得复杂，所述同种型通过使用交替启动子、差异剪接和不同的翻译后修饰在人类和啮齿动物中产生。几条证据表明，2类IGF-1亚型是专门为循环，支持IGF-1在正常生长过程中的内分泌作用。使用IGF-1基因外显子2的Cre/LoxP条件性基因靶向，我们在纯C57/BI 6遗传背景中产生了2类IGF-1敲除小鼠系，其中外显子2的特异性去除消除了2类IGF-1同种型。2类IGF-1基因敲除小鼠表现出正常的发育和出生后的生长模式，并有正常的IGF-1循环水平，由于1类转录的补偿性上调。相比之下，在相同的遗传背景下，缺乏外显子3的总IGF-1基因敲除系的后代可预见地更小，显示出显著降低的IGF-1受体磷酸化，并且都在围产期死亡，显然是由于呼吸衰竭。这些结果证实了2类信号肽对于IGF-1的体循环不是必需的，揭示了维持IFF-I血清浓度的内部补偿系统。我们还发现了一个重要的要求IGF-1围产期的生存能力，以前模糊的修饰剂在异质性遗传背景。(C)2010爱思唯尔有限公司保留所有权利。
Insulin-like growth factor 1 (IGF-1) is a pleiotropic factor involved in growth, cell survival and cellular differentiation. It exerts its functions through endocrine, paracrine or autocrine mechanisms. Circulating IGF-1 is essential for normal fetal and postnatal growth, although the published phenotypes of IGF-1 null animals have been only partially penetrant, presumably due to mixed genetic backgrounds. Molecular dissection of IGF-1 action is complicated by the existence of at least nine different IGF-1 isoforms, generated in both humans and rodents by usage of alternate promoters, differential splicing and different post-translational modifications. Several lines of evidence suggest that the Class 2 IGF-1 isoform is specifically destined for circulation, supporting an endocrine role of IGF-1 in normal growth processes. Using Cre/LoxP conditional gene targeting of exon 2 of the IGF-1 gene, we have generated a Class 2 IGF-1 knockout mouse line in a pure C57/BI6 genetic background, where the specific removal of exon 2 ablated Class 2 IGF-1 isoform. Class 2 IGF-1 knockout mice exhibited normal development and postnatal growth patterns and had normal IGF-1 circulating levels, due to compensatory upregulation of Class 1 transcripts. In contrast, progeny of a total IGF-1 knockout line lacking exon 3 in the same genetic background were predictably smaller, displayed dramatically reduced IGF-1 receptor phosphorylation and all died perinatally, apparently due to respiratory failure. These results confirm that Class 2 signal peptide is not necessary for systemic circulation of IGF-1, revealing an internal compensation system for maintaining IFF-1 serum concentrations. We also uncover a vital requirement of IGF-1 for perinatal viability, previously obscured by modifiers in heterogeneous genetic backgrounds. (C) 2010 Elsevier Ltd. All rights reserved.