SnoRNA Snord116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice
Feng Ding1, Hong Hua Li, Shengwen Zhang
1Department of Genetics, Stanford University, Stanford, California, USA.
Insights
Prader-Willi syndrome (PWS) is linked to the SNORD116 gene cluster. Mouse models lacking SNORD116 show growth deficiency, anxiety, and hyperphagia, revealing a role for non-coding RNA in PWS pathogenesis.
Area of Science:
- Genetics
- Neuroscience
- Endocrinology
Background:
- Prader-Willi syndrome (PWS) is a genetic disorder causing obesity, hypotonia, and cognitive issues.
- PWS results from the lack of imprinted gene expression in chromosome 15q11.2.
- The SNORD116 small nucleolar RNA cluster is a potential key player in PWS.
Purpose of the Study:
- To investigate the role of the SNORD116 gene cluster in PWS pathogenesis.
- To create and analyze a mouse model with a targeted deletion of SNORD116.
Main Methods:
- Generated a mouse model (Snord116del) with a ~150 kb deletion of the SNORD116 cluster.
- Assessed growth, fertility, lifespan, behavior, and metabolic parameters in Snord116del mice.
- Utilized metabolic chamber studies and measured circulating ghrelin levels.
Main Results:
- Snord116del mice exhibited postnatal growth deficiency, increased anxiety, and motor learning deficits.
- These mice developed hyperphagia around three months of age but remained lean.
- Altered fuel utilization and impaired meal termination mechanisms were observed, with prolonged mealtime and increased ghrelin.
Conclusions:
- The SNORD116 cluster plays a critical role in regulating growth, feeding behavior, and energy homeostasis.
- Snord116del mice represent the first animal model for a snoRNA deletion, offering insights into PWS.
- Non-coding RNAs like SNORD116 are novel targets for understanding and potentially treating PWS.
Abstract:
Prader-Willi syndrome (PWS) is the leading genetic cause of obesity. After initial severe hypotonia, PWS children become hyperphagic and morbidly obese, if intake is not restricted. Short stature with abnormal growth hormone secretion, hypogonadism, cognitive impairment, anxiety and behavior problems are other features. PWS is caused by lack of expression of imprinted genes in a approximately 4 mb region of chromosome band 15q11.2. Our previous translocation studies predicted a major role for the C/D box small nucleolar RNA cluster SNORD116 (PWCR1/HBII-85) in PWS. To test this hypothesis, we created a approximately 150 kb deletion of the > 40 copies of Snord116 (Pwcr1/MBII-85) in C57BL/6 mice. Snord116del mice with paternally derived deletion lack expression of this snoRNA. They have early-onset postnatal growth deficiency, but normal fertility and lifespan. While pituitary structure and somatotrophs are normal, liver Igf1 mRNA is decreased. In cognitive and behavior tests, Snord116del mice are deficient in motor learning and have increased anxiety. Around three months of age, they develop hyperphagia, but stay lean on regular and high-fat diet. On reduced caloric intake, Snord116del mice maintain their weight better than wild-type littermates, excluding increased energy requirement as a cause of hyperphagia. Normal compensatory feeding after fasting, and ability to maintain body temperature in the cold indicate normal energy homeostasis regulation. Metabolic chamber studies reveal that Snord116del mice maintain energy homeostasis by altered fuel usage. Prolonged mealtime and increased circulating ghrelin indicate a defect in meal termination mechanism. Snord116del mice, the first snoRNA deletion animal model, reveal a novel role for a non-coding RNA in growth and feeding regulation.
