Genomic Imprinting in Development and Disease

发育和疾病中的基因组印记

• 批准号: 6559233
• 负责人: COLIN STEWART
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6559233
• 关键词: cell growth regulation; cell proliferation; cyclin dependent kinase; developmental genetics; embryogenesis; enzyme inhibitors; gene expression; gene targeting; genetic disorder; genetically modified animals; genomic imprinting; growth factor receptors; insulinlike growth factor; laboratory mouse; mammalian embryology; tissue /cell culture

Unlike the majority of genes expressed in mammals, imprinted genes are expressed from only one parental allele- which allele depends on the particular gene. Thus the Insulin like growth factor 2 (Igf2) is expressed almost exclusively from the paternal allele, whereas p57Kip2, a CDK inhibitor is expressed from the maternal allele. This form of gene regulation is, among vertebrates, unique to mammals. Why it exists is still unclear. Much evidence has suggested that imprinted genes are involved in regulating cell proliferation and viability. Androgenetic embryos, in which the entire genome is paternal in origin, exhibit overgrowth of the extraembryonic membranes and in increase in fetal size at mid gestation. Parthenogenetic embryos, where the entire genome is maternal in origin show retarded embryonic growth. To facilitate an understanding of imprinting and to identify novel imprinted genes, we established fibroblast lines which are either exclusively androgenetic or parthenogenetic in origin. The lines show diametrically opposite patterns of growth with the androgenetic cells having a shorter cell cycle time, reaching a higher saturation density and forming tumors, whereas the parthenotes senesced and died. Using mouse lines deficient for imprinted genes such as Igf2, one of its receptors, the Igf2r, and p57Kip2 revealed that Igf2 was a major determinant regulating proliferation and viability of these cells. In addition to these growth studies, we have used these lines to identify novel imprinted genes. Using a suppressive subtractive screen we identified the nuclear receptor cofactor repressor/activator Zac1 and epsilon sarcoglycan as being imprinted genes expressed from the paternal allele, as well as an Est that is strongly expressed in the brain, and is transcribed from the maternal allele. Current studies are centered on determining the function of these genes in development and growth regulation. We are developing mouse models for a human congenital disease associated with a defect in imprinting called Prader-Willi syndrome. In this condition, newborns are hypotonic, have breathing difficulties and often fail to thrive. Those that survive develop an eating disorder and frequently become obese. The disease is associated with loss of part of the paternal chromosome 15. A homologous region is found on mouse chromosome 7. We recently described the derivation of mice lacking the paternal allele of a gene Necdin located in the Prader-Willi region. Such mice die shortly after birth due to respiratory problems and have mimicked one aspect of Prader-Willi syndrome. Their respiratory physiology is being studied in greater detail to determine the function of Necdin. Overall, a molecular analysis of imprinting should provide insights into the epigenetic control of gene expression, an aspect that is of increasing relevance to understanding the inactivation of certain tumor suppressor genes in cancer formation.

与哺乳动物中表达的大多数基因不同，印迹基因仅由一个亲本等位基因表达，而哪个等位基因取决于特定的基因。因此，胰岛素样生长因子2 （Igf2）几乎完全由父系等位基因表达，而CDK抑制剂p57Kip2则由母系等位基因表达。在脊椎动物中，这种形式的基因调控是哺乳动物所特有的。它存在的原因尚不清楚。大量证据表明，印迹基因参与调节细胞增殖和生存能力。在雄激素胚胎中，整个基因组来自父系，在妊娠中期表现出胚胎外膜的过度生长和胎儿大小的增加。孤雌生殖胚胎，其全部基因组来自母体，表现出胚胎发育迟缓。为了促进对印迹的理解和鉴定新的印迹基因，我们建立了纯雄激素或孤雌生殖的成纤维细胞系。细胞系表现出完全相反的生长模式，雄激素细胞周期短，达到较高的饱和密度并形成肿瘤，而孤雌细胞衰老和死亡。利用缺乏印迹基因（如Igf2）的小鼠系，其受体之一Igf2r和p57Kip2显示，Igf2是调节这些细胞增殖和活力的主要决定因素。