MOLECULAR CLONING OF THE MURINE LETHAL SPOTTING MUTATION

神经脊由侵袭的多能前体细胞组成。 胚胎的所有部分，并有助于广泛的阵列的发育 细胞和组织。神经脊细胞的异常表现多种多样 由于其不同的细胞潜力，表型的多样性。小鼠的致命性 点(Ls)突变作为研究相关因素的模型系统 在这些过程中，由于IS/ls小鼠的终末缺少肠神经节 由于黑素细胞的问题，他们的肠子和毛发上有白色斑点。 这种小鼠还提供了先天性巨结肠的遗传模型，一种 一种缺乏肠源性神经脊的人类疾病 远端结肠中的神经节。该基因的鉴定和分离 对IS突变负责是了解 它在神经脊细胞迁移、分化、存活和/或 以及理解其在疾病过程中的作用。我们 已经建立了IS的高分辨率分子遗传连锁图谱 利用亚种间回交分析和 确定了IS突变的图谱位置，我们将染色体走到 物理克隆IS区域。我们将开发必要的资源，以 从最小的部分识别和表征潜在的候选基因 必须包含IS基因的已定义间隔。这两种技术的结合 将采取的分子和遗传方法将提供基础 以全面了解IS基因及其功能。这 研究将提供对复杂的细胞相互作用的理解 在开发过程中发生的事件以及调查 IS基因在肿瘤发生中的潜在作用。

The neural crest is composed of multipotent precursor cells which invade all parts of the embryo and contribute to the development of a wide array of cell and tissues. Abnormalities of neural crest cells display a variety of phenotypes due to their diverse cellular potentials. The murine lethal spotting (ls) mutation serves as a model system to study factors involved in these processes, since Is/ls mice lack enteric ganglia in their terminal bowel and have white spots on their coat due to problems with melanocytes. This mouse also provides a genetic model for Hirschsprung's disease, a human disorder in which there is a lack of neural crest derived enteric ganglia in the distal colon. Identification and isolation of the gene responsible for the Is mutation is an important step towards understanding its role in neural crest cell migration, differentiation, survival, and/or function as well as for understanding its role in the disease process. We have established a high resolution molecular genetic linkage map of the Is region on mouse chromosome 2 using intersubspecific backcross analyses and determined the map position of Is mutation, we will chromosome walk to and physically clone the Is region. We will develop resources necessary to identify and characterize potential candidate genes from the smallest defined interval that must contain the Is gene. The combination of molecular and genetic approaches to be taken will provide the foundation for a comprehensive understanding of the Is gene and its functions. This research will provide an understanding of the complex cellular interactions occurring during development as well as an opportunity to investigate the potential role of the Is gene in neoplasia.