Dupont Joëlle, Holzenberger Martin
Institut National de la Recherche Agronomique, Centre National de la Recherche Scientifique, UMR 6073, Nouzilly, France.
Birth Defects Res C Embryo Today. 2003 Nov;69(4):257-71. doi: 10.1002/bdrc.10022.
Insulin-like growth factors (IGFs) provide essential signals for the control of embryonic and postnatal development in vertebrate species. In mammals, IGFs act through and are regulated by a system of receptors, binding proteins, and related proteases. In each of the many tissues dependent on this family of growth factors, this system generates a complex interaction specific to the tissue concerned. Studies carried out over the last decade, mostly with transgenic and gene knockout mouse models, have demonstrated considerable variety in the cell type-specific and developmental stage-specific functions of IGF signals. Brain, muscle, bone, cartilage, pancreas, ovary, skin, and fat tissue have been identified as major in vivo targets for IGFs. Concentrating on several of these organ systems, we review here phenotypic analyses of mice with genetically modified IGF systems. Much progress has also been made in understanding the specific intracellular signaling cascades initiated by the binding of circulating IGFs to their cognate receptor. We also summarize the most relevant aspects of this research. Considerable efforts are currently focused on deciphering the functional specificities of intracellular pathways, particularly the molecular mechanisms by which cells distinguish growth-stimulating insulin-like signals from metabolic insulin signals. Finally, there is a growing body of evidence implicating IGF signaling in lifespan control, and it has recently been shown that this function has been conserved throughout evolution. Very rapid progress in this domain seems to indicate that longevity may be subject to IGF-dependent neuroendocrine regulation and that certain periods of the life cycle may be particularly important in the determination of individual lifespan.
胰岛素样生长因子（IGFs）为脊椎动物胚胎期及出生后发育的控制提供关键信号。在哺乳动物中，IGFs通过一个由受体、结合蛋白及相关蛋白酶组成的系统发挥作用并受到其调节。在众多依赖该生长因子家族的组织中，该系统在各相关组织中产生复杂的特异性相互作用。过去十年开展的研究，大多使用转基因和基因敲除小鼠模型，已证明IGF信号在细胞类型特异性和发育阶段特异性功能方面具有相当大的多样性。脑、肌肉、骨骼、软骨、胰腺、卵巢、皮肤和脂肪组织已被确定为IGFs在体内的主要靶标。本文聚焦于其中几个器官系统，综述了IGF系统基因修饰小鼠的表型分析。在理解循环中的IGFs与其同源受体结合引发的特定细胞内信号级联反应方面也取得了很大进展。我们还总结了该研究中最相关的方面。目前相当多的研究工作集中在解读细胞内信号通路的功能特异性，特别是细胞区分生长刺激型胰岛素样信号与代谢型胰岛素信号的分子机制。最后，越来越多的证据表明IGF信号参与寿命控制，最近有研究表明该功能在整个进化过程中得以保留。该领域的飞速进展似乎表明，长寿可能受IGF依赖的神经内分泌调节，并且生命周期中的某些阶段在决定个体寿命方面可能尤为重要。
