Genetic Complementation of a Mouse Model for PWS

描述(申请人提供)：Prader-Willi综合征是一种神经行为障碍，以婴儿期低眼压、身材矮小和新生儿发育不良为特征，随后出现强迫行为、吞噬过度和肥胖。PWS是由位于15q11-13的几个印记基因的表达缺失引起的，可能是由于母亲的15q二体，父亲的一组PWS基因的缺失，或者父亲的微缺失去除了父亲基因表达所必需的印记中心(IC)。我们先前通过靶向删除IC的方法建立了PWS小鼠模型。携带父系IC缺失的幼崽无法茁壮成长，不可避免地会导致出生后第一周的死亡。在之前的资助期间，我们发现一些品系的母亲所生的IC缺失幼崽的死亡存活了下来，最终为研究PWS基因在成体以及胎儿和出生后阶段的作用提供了机会。PWS-IC缺失小鼠出生后早期死亡的病因很复杂。虽然不能茁壮成长是一个原因，但Necdin缺乏引起的呼吸问题也是一个重要因素。此外，我们还发现了多个基因座未能蓬勃发展的证据。在具体目标1中，我们将利用表达PWS基因组的BAC转基因互补来确定与发育失败相关的基因座，并确认Necdin在PWS小鼠模型出生后早期死亡中的作用。肥胖和潜在的吞噬功能亢进是PWS的显著特征。特定目的2建议探索在存活的成年PWS小鼠中发生肥胖的各种条件，并调查PWS基因在肥胖进展中的作用。已知有许多印记基因与胎儿生长有关。我们最近发现，IC缺失胚胎会降低胎儿的生长速度，并且一些PWS基因在胎盘中表达。在具体目标3中，我们将结合现有的PWS模型和BAC转基因互补来测试PWS基因亚组在胎盘发育中的作用。我们预计，这项研究将显著有助于理解单个基因在复杂的PWS特征中的作用，完善这种疾病的小鼠模型，并为生长和肥胖提供新的见解。

DESCRIPTION (provided by applicant): Prader-Willi syndrome is a neurobehavioral disorder characterized by infantile hypotonia, short stature, and neonatal failure to thrive followed by obsessive-compulsive behavior, hyperphagia, and obesity. PWS results from loss of expression of several imprinted genes located at 15q11-13 and can arise from maternal 15q disomy, paternal deletion of a group of PWS genes, or paternal microdeletions removing an imprinting center (IC) necessary for paternal gene expression. We previously created a PWS mouse model by targeted deletion of the IC. Pups bearing a paternal IC deletion exhibit a failure to thrive inevitably leading to death in the first postnatal week. In the previous funding period, we found that death of IC deletion pups born to mothers of some strains survive, finally providing an opportunity to investigate the role of PWS genes in adult, as well as fetal and postnatal stages. The etiology of early postnatal death in PWS-IC deletion mice is complex. While failure to thrive is one cause, respiratory problems caused by Necdin deficiency is also an important factor. Additionally, we have found evidence for multi-locus failure to thrive. In specific aim 1, we will use complementation by BAC transgenes expressing groups of PWS genes to identify loci involved in failure to thrive and to confirm the role of Necdin in early postnatal death in PWS mouse models. Obesity and underlying hyperphagia are salient aspects of PWS. Specific aim 2 proposes to explore various conditions to develop obesity in surviving adult PWS mice, and investigate the roles of PWS genes in progression to obesity. A number of imprinted genes are known to be involved in fetal growth. We have recently found that IC deletion embryos have decreased fetal growth and that some PWS genes are expressed in the placenta. In specific aim 3, we will combine existing PWS models and BAC transgene complementation to test the role of subsets of PWS genes in placental development. We anticipate that this research will significantly contribute to understanding the roles of individual genes in complex PWS traits, refine mouse models of the disease, and provide new insights into growth and obesity.