Ding Feng, Li Hong Hua, Zhang Shengwen, Solomon Nicola M, Camper Sally A, Cohen Pinchas, Francke Uta
Department of Genetics, Stanford University, Stanford, California, USA.
PLoS One. 2008 Mar 5;3(3):e1709. doi: 10.1371/journal.pone.0001709.
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.
普拉德-威利综合征（PWS）是肥胖的主要遗传病因。在最初出现严重的肌张力减退后，PWS患儿会变得食欲亢进并发展为病态肥胖，前提是摄入量不受限制。身材矮小、生长激素分泌异常、性腺功能减退、认知障碍、焦虑和行为问题是其他特征。PWS是由染色体15q11.2带约4 Mb区域内印记基因的表达缺失引起的。我们之前的易位研究预测C/D盒小核仁RNA簇SNORD116（PWCR1/HBII-85）在PWS中起主要作用。为了验证这一假设，我们在C57BL/6小鼠中创建了一个约150 kb的缺失，涉及超过40个拷贝的Snord116（Pwcr1/MBII-85）。父源缺失的Snord116del小鼠缺乏这种小核仁RNA的表达。它们出生后早期出现生长发育迟缓，但生育能力和寿命正常。虽然垂体结构和生长激素细胞正常，但肝脏Igf1 mRNA水平降低。在认知和行为测试中，Snord116del小鼠运动学习能力不足且焦虑增加。大约三个月大时，它们出现食欲亢进，但在常规饮食和高脂饮食下仍保持消瘦。在热量摄入减少的情况下，Snord116del小鼠比野生型同窝小鼠体重维持得更好，排除了能量需求增加作为食欲亢进原因的可能性。禁食后正常的代偿性进食以及在寒冷环境中维持体温的能力表明能量稳态调节正常。代谢室研究表明，Snord116del小鼠通过改变燃料使用来维持能量稳态。进餐时间延长和循环胃饥饿素增加表明进餐终止机制存在缺陷。Snord116del小鼠是首个小核仁RNA缺失动物模型，揭示了一种非编码RNA在生长和进食调节中的新作用。
