GROWTH RELATED GENES ON CHROMOSOME 11P155

描述（申请人的描述）：基因组印记导致 某些基因的来源亲本依赖性单等位基因表达， 后代 理论论据和有限的实验数据表明， 一个不成比例的印记基因的数量可能涉及在 控制胎儿和胎盘的生长。 低分辨率绘图和 机械模型表明，基因组印记可能是区域性的， 含有印记基因簇的特定染色体片段。 印记的这两个特征可以帮助解释 印记染色体区域在某些人类胚胎发育异常的发病机制中的作用 肿瘤的 申请人实验室的一个主要兴趣是测试 染色体11p15.5上存在一个扩展的印迹结构域的假说 在这个染色体区域有多个印记基因， 有助于正常生长控制和胚胎肿瘤发生。 的 申请人组装了跨越700 Kb染色体的克隆重叠群 11p15.5。 该重叠群位于最小区域内， 母源性等位基因在肾母细胞瘤（WT），包括几个已知的印迹 基因. 该重叠群的外显子捕获发现了6个新基因， 基因隔离工作正在进行。 这些基因中的第一个 选择用于分析，IPL（印在胎盘和肝脏），编码一个主要的 胎盘转录本 该基因的预测蛋白产物显示， 与淋巴细胞转录物TDAG 51的序列相似性，TDAG 51似乎是 参与使细胞易于凋亡。 他们发现 IPL基因在人胎盘中是单等位基因表达的， 可能反映了父母的印记 虽然IPL不太可能是WT 基因，它可以调节正常胎盘的生长，因此也可以发挥作用。 在胎盘瘤形成中的作用。 目前的建议是调查 IPL基因的生物学作用，并分离和表征其他 来自染色体11p15.5这一区域的印记基因， 胎儿和胎盘 在目标1中，申请人将分离小鼠 IPL基因的直系同源物，他们将测试小鼠Ip 1的印记 使用种间小鼠杂交，他们将确定其内含子/外显子 结构 在目标2中，他们将描述 小鼠和人IPL基因的原位杂交研究， 表达系统，并通过构建种系缺失小鼠。 在目标3 他们将把IPL的分析扩展到人类胎盘肿瘤， 组织中 在目标4中，他们将从他们的基因中分离出额外的印记基因。 染色体11p15.5克隆重叠群，并研究它们对 正常胎儿和胎盘生长的方法类似于那些描述 IPL基因。

DESCRIPTION (Applicant's Description): Genomic imprinting results in parent-of-origin dependent monoallelic expression of certain genes in the offspring. T h e o retical arguments and limited experimental data suggest that a disproportionate number of imprinted genes may be involved in the control of fetal and placental growth. Low-resolution mapping and mechanistic models suggest that genomic imprinting may be regional, with particular chromosomal segments containing clusters of imprinted genes. These two features of imprinting could help to explain the involvement of imprinted chromosomal regions in the pathogenesis of certain human embryonal tumors. A major interest of the applicants' laboratory is to test the hypothesis that there is an extended imprinted domain on chromosome 11p15.5 and that there are multiple imprinted genes in this chromosomal region which contribute to normal growth control and embryonal tumorigenesis. The applicants have assembled a clone contig spanning 700 Kb of chromosome 11p15.5. This contig lies within the minimal region subject to loss of maternal alleles in Wilms' tumor (WT) and includes several known imprinted genes. Exon-trapping of this contig has uncovered 6 new genes, and gene-isolation efforts are ongoing. The first of these genes which they chose for analysis, IPL (imprinted in placenta and liver), encodes a major placental transcript. The predicted protein product of this gene shows sequence similarity to a lymphocyte transcript, TDAG51, which appears to be involved in rendering cells susceptible to apoptosis. They have found that the IPL gene is monoallelically expressed in human placenta, and this is likely to reflect parental imprinting. While IPL is not likely to be a WT gene, it may regulate growth of the normal placenta, and may thus also play a role in placental neoplasia. The current proposal is to investigate the biological role of the IPL gene and to isolate and characterize additional imprinted genes from this region of chromosome 11p15.5 which regulate growth of the fetus and placenta. In Aim 1 the applicants will isolate the mouse orthologue of the IPL gene, they will test the imprinting of murine Ip1 using interspecific mouse crosses and they will determine its intron/exon structure. In Aim 2 they will characterize the biological function of the mouse and human IPL gene by in situ hybridization studies, by eukaryotic expression systems, and by construction of germline-deletion mice. In Aim 3 they will extend their analysis of IPL to neoplastic human placental tissues. In Aim 4 they will isolate additional imprinted genes from their chromosome 11p15.5 clone contig and study them in terms of their effects on normal fetal and placental growth by approaches similar to those described for the IPL gene.