Antagonistic roles in fetal development and adult physiology for the oppositely imprinted Grb10 and Dlk1 genes.
Antagonistic roles in fetal development and adult physiology for the oppositely imprinted Grb10 and Dlk1 genes.
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DOI：
10.1186/s12915-014-0099-8
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发表时间：
2014-12-31
期刊：
影响因子：
5.4
通讯作者：
Ward A
中科院分区：
文献类型：
--
作者：
Madon-Simon M;Cowley M;Garfield AS;Moorwood K;Bauer SR;Ward A
尽管胰岛素样生长因子(IGF)途径在生长调节中起着核心作用，但在发育过程中对身体大小和比例的控制仍然知之甚少，尽管这是一个基本的生物学问题，可能在所有动物中。印记基因的参与也引起了很多关注，尤其是因为最早发现的两个基因被证明是相反的印记，并且在它们对生长的调节方面具有拮抗作用。Igf2基因编码父系表达的促进生长的配体，而母体表达的Igf2r编码一种细胞表面受体，通过隔离Igf2并将其靶向于溶酶体降解来限制生长。目前在哺乳动物中已知的印迹基因有150多个，但还没有发现其他明显的拮抗基因对。Delta-like 1基因(Dlk1)编码一种可能的配体，促进胎儿生长，并在成年人中限制脂肪沉积。相反，Grb10编码一种细胞内信号转接蛋白，当从母体等位基因表达时，该蛋白会限制胎儿的生长，并允许成年后脂肪沉积。在这里，利用基因敲除小鼠，我们提出了遗传和生理学证据，证明这两个因素通过共同的信号通路对生长和生理产生相反的影响。主要的影响是对身体大小(特别是在生命早期的生长)、瘦肉：脂肪比例、葡萄糖调节的代谢和肝脏中的脂肪储存。连接这两个细胞信号因子的生化途径仍有待确定。我们认为Dlk1和Grb10定义了一个独立于IGF途径的哺乳动物生长轴，但也以一对拮抗印记基因对为特征。本文的在线版本(doi：10.1186/s12915-0140099-8)包含补充材料，授权用户可以使用。
Despite being a fundamental biological problem the control of body size and proportions during development remains poorly understood, although it is accepted that the insulin-like growth factor (IGF) pathway has a central role in growth regulation, probably in all animals. The involvement of imprinted genes has also attracted much attention, not least because two of the earliest discovered were shown to be oppositely imprinted and antagonistic in their regulation of growth. The Igf2 gene encodes a paternally expressed ligand that promotes growth, while maternally expressed Igf2r encodes a cell surface receptor that restricts growth by sequestering Igf2 and targeting it for lysosomal degradation. There are now over 150 imprinted genes known in mammals, but no other clear examples of antagonistic gene pairs have been identified. The delta-like 1 gene (Dlk1) encodes a putative ligand that promotes fetal growth and in adults restricts adipose deposition. Conversely, Grb10 encodes an intracellular signalling adaptor protein that, when expressed from the maternal allele, acts to restrict fetal growth and is permissive for adipose deposition in adulthood. Here, using knockout mice, we present genetic and physiological evidence that these two factors exert their opposite effects on growth and physiology through a common signalling pathway. The major effects are on body size (particularly growth during early life), lean:adipose proportions, glucose regulated metabolism and lipid storage in the liver. A biochemical pathway linking the two cell signalling factors remains to be defined. We propose that Dlk1 and Grb10 define a mammalian growth axis that is separate from the IGF pathway, yet also features an antagonistic imprinted gene pair. The online version of this article (doi:10.1186/s12915-014-0099-8) contains supplementary material, which is available to authorized users.
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DOI：
10.1073/pnas.1532175100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Charalambous, M;Smith, FM;Ward, A
通讯作者：
Ward, A
影响因子：
9.2
作者：
Brogiolo, W;Stocker, H;Hafen, E
通讯作者：
Hafen, E
影响因子：
64.5
作者：
BAKER, J;LIU, JP;EFSTRATIADIS, A
通讯作者：
EFSTRATIADIS, A
影响因子：
64.8
作者：
FERGUSONSMITH, AC;SASAKI, H;SURANI, MA
通讯作者：
SURANI, MA
影响因子：
64.8
作者：
BARTOLOMEI, MS;ZEMEL, S;TILGHMAN, SM
通讯作者：
TILGHMAN, SM