Imprinted genes defining a novel growth regulatory axis

印记基因定义了新的生长调节轴

• 批准号: MR/S008233/1
• 负责人: Andrew Ward
• 金额: $ 58.92万
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS008233%2F1
• 关键词: Imprinted; genes; defining; novel; growth

Correct growth during life in the womb is important for infant survival and is also known to impact health throughout life, including the risk of developing common metabolic disorders such as obesity, diabetes and heart disease. Growth is a highly regulated process but basic questions remain unanswered such as: How are appropriate body size and proportions achieved? Which genes are important and how do they link fetal growth with lifelong health? Through genetic studies in mice we have identified two genes involved in regulating fetal growth that also influence the balance of lean and adipose tissue in later life, along with other aspects of metabolic health. One of these genes, Dlk1, promotes fetal growth and limits adipose accumulation, whereas Grb10 restricts growth and promotes adipose deposition. We have strong evidence that the two genes influence these processes in opposite directions by acting antagonistically in the same regulatory circuit (or pathway). Such regulation, involving positive and negative factors to achieve fine control, is typical of biological systems. Our next goal is to identify other key components of the Dlk1/Grb10 pathway. Towards this aim, we have constructed a model of how the pathway might work, based on our own studies and those of others in the field. For instance, we know that while Grb10 directly inhibits growth, Dlk1 promotes growth indirectly by inhibiting Grb10. Also, quite a lot is known about the proteins encoded by the Dlk1 and Grb10 genes, from which we can infer the types of molecule they must interact with. In fact each interacts with different cell surface receptor molecules, akin to antennae projecting out from the cell membrane. Dlk1 encodes a signal protein released from one cell that interacts with receptors projecting from another. This type of cell to cell communication is important for coordinating the complex processes of growth and development. Grb10 encodes a molecule that interacts with receptors from within the cell, where it acts to modify how the cell responds to signals coming from the outside. In the case of Grb10 we have identified a strong candidate 'growth' receptor and one of our key goals is to validate and investigate this candidate further. Similarly, we have a candidate protein predicted to inhibit Grb10 as a consequence of Dlk1 signalling, and we will carry out experiments to test the interaction between the inhibitor and Grb10. These candidate molecules represent key components of the pathway, their validation would confirm important mechanisms predicted by our model and would provide the evidence needed to firmly establish the Dlk1/Grb10 growth axis. Finally, we have designed experiments that will enable us to discover additional pathway components, or alternatives should either of the candidates prove false. Our studies indicate that the pathway involving Dlk1 and Grb10 is novel and important for our understanding of fetal growth regulation. Further, knowledge of this pathway would impact the future development of advice and treatments to prevent growth and metabolic disorders.

在子宫内生活期间的正确生长对于婴儿的生存非常重要，并且还已知会影响一生的健康，包括患上肥胖症，糖尿病和心脏病等常见代谢疾病的风险。生长是一个高度调节的过程，但基本的问题仍然没有答案，如：如何达到适当的身体大小和比例？哪些基因是重要的，它们如何将胎儿生长与终身健康联系起来？通过对小鼠的遗传研究，我们已经确定了两个参与调节胎儿生长的基因，这两个基因也会影响晚年瘦肉和脂肪组织的平衡，沿着代谢健康的其他方面。其中一个基因Dlk 1促进胎儿生长并限制脂肪积累，而Grb 10限制生长并促进脂肪沉积。我们有强有力的证据表明，这两个基因通过在相同的调节回路（或途径）中拮抗作用，以相反的方向影响这些过程。这种调节涉及积极和消极因素以实现精细控制，是生物系统的典型特征。 我们的下一个目标是确定Dlk 1/Grb 10通路的其他关键组分。为了实现这一目标，我们已经建立了一个模型，如何途径可能会工作，基于我们自己的研究和其他人在该领域。例如，我们知道Grb 10直接抑制生长，而Dlk 1通过抑制Grb 10间接促进生长。此外，人们对Dlk 1和Grb 10基因编码的蛋白质也有很多了解，从中我们可以推断出它们必须与之相互作用的分子类型。事实上，每一种都与不同的细胞表面受体分子相互作用，类似于从细胞膜伸出的天线。dlk 1编码一种从一个细胞释放的信号蛋白，该信号蛋白与从另一个细胞投射的受体相互作用。这种类型的细胞间通讯对于协调生长和发育的复杂过程非常重要。grb 10编码一种与细胞内受体相互作用的分子，在那里它可以改变细胞对来自外部信号的反应方式。在Grb 10的情况下，我们已经确定了一个强有力的候选“生长”受体，我们的主要目标之一是进一步验证和研究这个候选受体。类似地，我们有一个候选蛋白预测抑制Grb 10作为Dlk 1信号传导的结果，我们将进行实验来测试抑制剂和Grb 10之间的相互作用。这些候选分子代表了该途径的关键组成部分，它们的验证将证实我们模型预测的重要机制，并将提供牢固建立Dlk 1/Grb 10生长轴所需的证据。最后，我们设计了实验，使我们能够发现额外的途径组件，或替代方案，如果任何一个候选人被证明是错误的。我们的研究表明，涉及Dlk 1和Grb 10的途径是新的，对我们了解胎儿生长调节很重要。此外，对这一途径的了解将影响预防生长和代谢紊乱的建议和治疗的未来发展。

项目成果

Mice lacking paternal expression of imprinted Grb10 are risk-takers.

• DOI: 10.1111/gbb.12679
• 发表时间: 2020-09
• 期刊: Genes, brain, and behavior

Imprinted Grb10, encoding growth factor receptor bound protein 10, regulates fetal growth independently of the insulin-like growth factor type 1 receptor (Igf1r) and insulin receptor (Insr) genes

• DOI: 10.1101/2024.01.24.576998
• 发表时间: 2024-01
• 期刊: BMC Biology
• 影响因子: 5.4
• 作者: K. Moorwood;Florentia M. Smith;Alastair S. Garfield;Andrew Ward

Mice carrying paternal knockout of imprinted Grb10 do not show compulsive behaviour

携带父亲印记 Grb10 基因敲除的小鼠不会表现出强迫行为

• DOI: 10.1101/2020.04.03.016014
• 发表时间: 2020
• 作者: Rienecker K

Mice lacking paternal expression of imprinted Grb10 are risk-takers

缺乏印记 Grb10 父系表达的小鼠是冒险者

• DOI: 10.1101/2020.02.25.962399
• 发表时间: 2020
• 作者: Dent C

Imprinted Gene Expression and Function of the Dopa Decarboxylase Gene in the Developing Heart.

• DOI: 10.3389/fcell.2021.676543
• 发表时间: 2021
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Prickett AR;Montibus B;Barkas N;Amante SM;Franco MM;Cowley M;Puszyk W;Shannon MF;Irving MD;Madon-Simon M;Ward A;Schulz R;Baldwin HS;Oakey RJ
• 通讯作者: Oakey RJ