Developmental programming mediated by complementary roles of imprinted Grb10 in mother and pup.
Developmental programming mediated by complementary roles of imprinted Grb10 in mother and pup.
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DOI：
10.1371/journal.pbio.1001799
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发表时间：
2014-02
期刊：
影响因子：
9.8
通讯作者：
Ward A
中科院分区：
文献类型：
--
作者：
Cowley M;Garfield AS;Madon-Simon M;Charalambous M;Clarkson RW;Smalley MJ;Kendrick H;Isles AR;Parry AJ;Carney S;Oakey RJ;Heisler LK;Moorwood K;Wolf JB;Ward A
一项小鼠遗传研究表明，在通过胎盘和乳腺提供营养的独特哺乳动物现象中，一个作用于母亲和后代的单一基因起着核心作用。发展规划将生命早期的成长与成年后的健康状况联系起来。虽然环境因素，如母亲的饮食可以影响后代的生长和成年健康状况，但遗传对这一过程的影响尚不清楚。以小鼠为模型，我们确定了印迹基因Grb10作为产后营养供需的中介。Grb10在母体中表达，控制供给，与Grb10在子代中表达，控制需求，共同作用调控子代生长。此外，Grb10决定发育过程中瘦肉和脂肪组织的比例，从而影响成人的能量稳态。最引人注目的是，我们发现正常瘦/胖比例的发育取决于母亲表达的Grb10和后代表达的Grb10的综合作用，前者对后代肥胖的影响更大，后者影响瘦质量。Grb10在母鼠和幼崽中的这些不同功能是互补的，这与印迹进化的共同适应模型相一致，该模型是可以预测的，但实验证据有限。此外，我们的研究结果确定Grb10是发育规划的关键遗传组成部分，并强调需要在遗传水平上更好地了解母亲-后代相互作用，以预测成人疾病风险。早期生活经历可影响成年后的健康状况；例如，出生体重过低会增加日后患糖尿病和肥胖的风险。这种发育过程可能受到饮食等环境因素的影响，但基因在这一过程中的重要性尚不清楚。以小鼠为模型，我们研究了基因Grb10，它是印迹的，这意味着它只从它的两个拷贝中的一个拷贝表达。我们发现Grb10是发育编程的关键中介，控制出生后营养物质的供应和需求，影响生长和身体组成。具体来说，我们发现Grb10决定了发育过程中瘦肉组织和脂肪组织的比例，这取决于Grb10在母亲和后代中的共同作用。我们的发现有两个主要含义。首先，他们认为Grb10在母亲和后代中的功能是共同适应的，为印迹基因进化的共同适应模型提供了支持。其次，他们强调，如果我们要更全面地了解肥胖等复杂成人疾病的原因，就需要更好地掌握母体和后代基因在发育过程中是如何相互作用的。
A mouse genetic study reveals that a single gene acting in both mother and offspring has a central role in the uniquely mammalian phenomenon of nutrient provisioning through the placenta and the mammary gland. Developmental programming links growth in early life with health status in adulthood. Although environmental factors such as maternal diet can influence the growth and adult health status of offspring, the genetic influences on this process are poorly understood. Using the mouse as a model, we identify the imprinted gene Grb10 as a mediator of nutrient supply and demand in the postnatal period. The combined actions of Grb10 expressed in the mother, controlling supply, and Grb10 expressed in the offspring, controlling demand, jointly regulate offspring growth. Furthermore, Grb10 determines the proportions of lean and fat tissue during development, thereby influencing energy homeostasis in the adult. Most strikingly, we show that the development of normal lean/fat proportions depends on the combined effects of Grb10 expressed in the mother, which has the greater effect on offspring adiposity, and Grb10 expressed in the offspring, which influences lean mass. These distinct functions of Grb10 in mother and pup act complementarily, which is consistent with a coadaptation model of imprinting evolution, a model predicted but for which there is limited experimental evidence. In addition, our findings identify Grb10 as a key genetic component of developmental programming, and highlight the need for a better understanding of mother-offspring interactions at the genetic level in predicting adult disease risk. Experiences during early life can impact on health status in adulthood; low birth weight, for example, is linked to an increased risk of diabetes and obesity in later life. Such developmental programming can be influenced by environmental factors such as diet, but the importance of genetics in this process is not well understood. Using the mouse as a model, we investigate the gene Grb10, which is imprinted, meaning that it is expressed from only one of its two copies. We show that Grb10 is a key mediator of developmental programming, controlling supply and demand of nutrients in the postnatal period and influencing growth and body composition. Specifically, we find that Grb10 determines the proportions of lean and fat tissue during development, and that this is dependent on the combined actions of Grb10 in the mother and offspring. Our findings have two main implications. First, they suggest that the functions of Grb10 in mother and offspring are coadapted, providing support for a coadaptation model for the evolution of imprinted genes. Second, they highlight the need for a better grasp of how maternal and offspring genetics interact during development if we are to understand more fully the causes of complex adult disorders such as obesity.
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