The function of the imprinted microRNA-483 in growth, metabolism and cancer

MicroRNAs are small molecules that control the amount of proteins that the body makes, as well as the timing that these proteins are made. Because of this action they are very important for development and the health of organisms. The precise function of many microRNAs, estimated to be in their hundreds in humans, is unknown. Many of these small molecules are made from inside genes and they are dependent on those genes machinery to be produced. MiR-483 is a microRNA that is produced by the machinery that makes an important growth factor in the body called Igf2. We know what Igf2 does, it promotes growth and is also involved in how much fat and sugar we can store, but nothing is known about its partner microRNA. We have made an interesting observation: when we make a mouse that does not have the microRNA, but still makes the growth factor Igf2 normally, this results in postnatal overgrowth (the genetically engineered mice are about 10% heavier than their brothers and sisters that were not engineered). This exciting results suggests that the main function of this microRNA is to put the brakes on growth, a function that is precisely the opposite of its host gene! We now want to find out more about this microRNA - what else does it do in addition to regulate postnatal growth? Is it involved in the many ways we control fat and sugar storage and how we use those stores? Does it have a role in diseases of growth such as cancer? What genes and proteins does this microRNA help to control? Can we find precisely how it works? This project is important because it can give us new clues on how microRNAs work, in particular in growth control (as far as we know this is the first example of an microRNA involved in control of body size). If it turns out that its normal function is indeed to put down the brakes on growth it will be very important to consider using it as an anti-cancer therapy. Other diseases of growth control, such as those that lead to smaller babies and big babies, with and without postnatal growth compensation may also benefit from our research.

Growth is essential for life. Regulation of growth of an organism in relation to its environment is pivotal for evolutionary success and fitness. Related and similarly important is the regulation of the size of the individual organs in the body in relation to each other and to the size of the whole organism. The pathway in which the Growth Hormone/Insulin-like growth factor 1 axis participates provides the main conduit of growth control as evidenced by mouse genetic experiments. It is estimated that only 17% of the total body size of an adult mouse can be attained without the participation of GH and IGF1. Finding growth control mechanisms that are independent of the circuitry involving GH/IGF1 is an important basic research topic, with important clinical applications. MicroRNAs are a large family of post-transcriptional regulators of gene expression that are ~21 nucleotides in length. A single miRNA may act as a master control of gene expression through regulation of multiple targets. Up to a third of microRNA genes are intronic and transcribed along theirs host genes. The major fetal growth factor IGF2 locus harbors a microRNA (miR-483). We recently tested the potential activity of miR-483 as a growth control microRNA by generating a knock-out mouse. Our results provide evidence for an important role of miR-483 in early postnatal body size and organ growth control. To our knowledge miR-483 constitutes the first example of a growth control miRNA. This proposal aims to seek the molecular pathways underlying growth repression by miR-483. We will explore the idea that miR-483 may interfere with previously undescribed genetic pathways that control growth. This work will yield important novel insights into the genetics of growth and cell proliferation diseases such as cancer, in addition to contributing to our understanding of the evolution of genomic imprintin

Growth is essential for life. Being the right size in different circumstances and environments can crucially affect survival and reproductive success. Growth is thus an area of interest to a diverse group of beneficiaries including the general public, scientists, health care professionals and policy makers. For example, Intra-uterine growth restriction (IUGR) is a complication that affects 3% of all pregnancies and results from the fetus failing to achieve its genetically determined growth potential. Low birth weight is a major cause of neonatal morbidity and mortality and is associated with later life risk of type 2 diabetes and cardiovascular disease. Identifying the key mechanisms by which growth trajectories are normally maintained and regulated, and of the pathological processes leading to abnormal growth, would be of considerable benefit to improving health. This project will address the contributions of an imprinted microRNA for growth, cellular proliferation and cancer using mouse models, with expected significant new insights for human growth conditions and cancer with diagnostic and potentially therapeutic value. Pregnant women and cancer patients are therefore likely important beneficiaries. The findings of the current study will be disseminated through multiple channels and to multiple target audiences to ensure maximum cost benefit.

The general public will be informed via press and broadcast media following joint press releases by the University of Cambridge press office in consultation with the MRC. The applicant has considerable experience in public dissemination of his group's findings. Dr Constancia has frequent contact with the media including TV, radio and magazines and has given public lectures. Dr Constancia's group are involved in activities run by the University of Cambridge during National Science week and every year he hosts a couple of undergraduate students, from the UK and Europe, in his laboratory.

Peer reviewed publications in the scientific literature as well as international conference presentations will be the main route by which findings are disseminated to the scientific community. Dr Constancia is a member of the Centre for Trophoblast Research that will provide a further route for dissemination to individuals with an interest in imprinting, epigenetics, growth disorders and cancer. Dr. Constancia is regularly invited to present lectures at international conferences, including those aimed at research scientist as well as clinicians and health care professionals. He also give lectures to both undergraduate and graduate students.