使用Cre/loxP系统条件敲除小鼠胰岛素样生长因子-1基因。

Jun-li Liu, S. Yakar, Derek Leroith
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引用次数: 79

摘要

胰岛素样生长因子-1 (Insulin-like growth factor-1, IGF-1)是正常宫内发育和产后生长的重要生长因子。通过同源重组产生的完全缺乏IGF-1的小鼠(IGF-1缺失小鼠)表现出出生后死亡、生长迟缓、不育和主要器官系统发育的严重缺陷。此外,igf -1缺失小鼠在青春期前期体细胞生长过程中对生长激素(GH)产生抗性。使用Cre/ loxp诱导的条件敲除系统,我们产生了在肝脏特异性缺乏IGF-1的小鼠,肝脏是IGF-1产生的主要部位。有趣的是,尽管这些小鼠的循环和血清IGF-1水平下降了大约75%,但它们的生长或发育没有出现缺陷。当外源性给药时,生长激素刺激了几种肝外组织中IGF-1的产生以及身体生长。“生长激素假说”最初提出,循环IGF-1在各种组织中作用介导生长激素的作用。使用同源重组技术获得的这些惊人的体内结果要求对生长抑素假说进行重大修改。这些基因靶向研究证实,IGF-1对gh刺激的出生后身体生长至关重要。然而,肝源性(内分泌)IGF-1对正常的出生后生长并不是必需的,尽管它确实对生长激素的分泌有负反馈作用。相反,IGF-1的局部产生,以旁分泌/自分泌方式起作用,似乎介导gh诱导的体细胞生长。这篇综述将讨论由Cre/loxP系统产生的组织特异性IGF-1基因缺陷与常规IGF-1敲除的影响。
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Conditional knockout of mouse insulin-like growth factor-1 gene using the Cre/loxP system.
Insulin-like growth factor-1 (IGF-1) is an essential growth factor for normal intrauterine development and postnatal growth. Mice with a complete deficiency of IGF-1 (IGF-1-null mice), created by homologous recombination, were found to exhibit postnatal lethality, growth retardation, infertility, and profound defects in the development of major organ systems. Furthermore, IGF-1-null mice were resistant to growth hormone (GH) treatment in peri-pubertal somatic growth. Using the Cre/loxP-induced conditional knockout system, we generated a mouse that lacks IGF-1 specifically in the liver, the primary site of IGF-1 production. Interestingly, although circulating and serum levels of IGF-1 were decreased by approximately 75% in these mice, they exhibited no defect in growth or development. When administered exogenously, GH stimulated IGF-1 production in several extra-hepatic tissues as well as body growth. The "Somatomedin hypothesis" originally proposed that circulating IGF-1 acting in various tissues mediate the effects of GH. These striking in vivo results, obtained using homologous recombination technology, call for a major modification of the Somatomedin hypothesis. These gene targeting studies confirm that IGF-1 is essential for GH-stimulated postnatal body growth. However, liver-derived (endocrine) IGF-1 is not essential for normal postnatal growth, though it does exert a negative feedback on GH secretion. Instead, local production of IGF-1, acting in a paracrine/autocrine fashion, appears to mediate GH-induced somatic growth. This review will discuss the effects of tissue-specific IGF-1 gene deficiency created by the Cre/loxP system versus the conventional IGF-1 knockout.
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