Abstract
The role of the brain in controlling food intake is increasingly apparent, with studies finding that genes related to obesity often play a role in brain regions crucial for feeding, appetite, and satiety. Prader-Willi syndrome, one of the most common forms of genetic obesity, results increased food intake (hyperphagia) leading to severe obesity, as well mental retardation, infertility, and short stature. Prader-Willi Syndrome is known to be caused by deletions on human chromosome 15, which has been recently narrowed down to encompass of a cluster of non-coding RNAs called SNORD116. Whenever studying the brain, animal models are required, very often mice, because we clearly cannot get into the brain of a living human. The problem with mouse models of PWS to date however, including those in which Snord116 have been deleted, is they don’t display hyperphagia and obesity. In fact, they are actually born smaller and remain smaller than normal mice all through life. In a major breakthrough, we have shown that if you delete Snord116 in mice as an adult, then the mice do display the hallmark PWS feature of hyperphagia. However, currently, only some of these mice become obese, and we would like to know why. Also, while the SNORD116 cluster exists in both mice and humans, in mice all of the copies of Snord116 are all nearly identical, whereas in humans, they are split into three different groups. We would like to know if each of these subgroups of human SNORD116 contributes differently to PWS. We will do this by using modern gene editing techniques to selectively delete each different subgroup in human stem-cells, before differentiating them into neurons. We thus hope to provide new insights into how deficiency of Snord116 affects the brain control of food intake, and provide the PWS research community with new models to investigate the hallmark phenotypes of obesity and hyperphagia associated with PWS.
Learn More!
Dr. Theresa Strong describes this grant, why we are excited about it and what the long term contributions of this project may be in our Research Grants Program Update Webinar, Spring 2018. You can learn more about this specific project in this video segment.
Research Outcomes: Public Summary
The work performed during this grant cycle was largely about generating resources. With increasing attention on the Snord116 cluster as a central player in the pathophysiology of PWS, comes the imperative to better understand these orphan non-coding RNAs. The human stem-cells with targeted deletion of each of the three groups of Snord116 are unique for four reasons.
1) The human cluster, with its three different groups, is substantively different from the single mouse cluster, so to truly understand the role of Snord116, we have to study it in a human context;
2) These deletions are being performed in a single cell-line, so are isogenic, allowing for analyses without genetic noise;
3) These stem-cells can be converted into hypothalamic neurons, allowing us to study the role of Snord116 in the most relevant cellular context;
4) These will be the first resources that allow for the study of each grouping of Snord116s separately.
Research Outcomes: Publications
Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi Syndrome. Polex-Wolf J, Lam BYH, Larder R, Tadross J, Rimmington D, Bosch F, Cenzano VJ, Eduard Ayuso E, Ma MKL, Rainbow K, Coll AP, O’Rahilly S, Yeo GSH. (2018) J. Clin. Invest. 128(3):960-969. Epub 2018 Jan 29
Funded Year:
2018
Awarded to:
Giles Yeo, PhD
Amount:
$64,800
Institution:
University of Cambridge
