Consequences of targeted SNORD116 deletion in human and mouse neurons

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.

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