Imprinted genes defining a novel growth regulatory axis

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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.