DEVELOPMENTAL FUNCTION OF THE C-RET PROTO-ONCOGENE

本项目的目标是阐明 由c-ret原癌基因编码的受体酪氨酸激酶（RTK）。 RTK，其中许多可以作为癌基因后重排或病毒 转导，通常作为细胞受体的各种 生长和分化因子在发育中具有重要作用。 c-ret基因，首先以其重排的致癌形式被发现， 似乎编码一种尚未鉴定的配体的受体。 在 在小鼠胚胎中，c-ret mRNA在早期迁移的细胞中表达。 神经嵴细胞及其神经元衍生物，在区域的 中枢神经系统，以及发育中的排泄系统， 特别是在肾管、输尿管芽和生长尖 收集管道的。 新生小鼠的突变等位基因纯合子 在胚胎干中通过基因打靶产生c-ret基因，ret-k-， 细胞，缺乏肠神经系统，并显示双侧肾 发育不全或发育不良。 因此，ret蛋白必须发挥重要作用， 在细胞迁移、增殖、分化或存活中的作用 肠神经元祖细胞及其衍生物，以及在 肾脏的器官形成，可能是作为受体， 信号分子的发展所需的排泄， 系统和肠神经系统。 我们建议研究 c-ret基因在这些发育过程中的功能， 对ret-k突变小鼠的一系列研究，以及通过 产生额外的突变和转基因小鼠品系。 在 此外，我们将尝试鉴定和克隆编码 c-ret受体的配体。 我们提出的战略基于 配体作为细胞表达的生长因子的潜力 外源性c-ret受体基因。 这项工作与我们的 了解癌基因和原癌基因之间的关系， 同时也应该提供了新的分子机制 控制哺乳动物神经和排泄系统的发育。

The goal of this project is to elucidate the developmental function of the receptor tyrosine kinase (RTK) encoded by the c-ret proto-oncogene. RTKs, many of which can act as oncogenes following rearrangement or viral transduction, normally serve as the cellular receptors for a variety of growth and differentiation factors with important roles in development. The c-ret gene, first identified in its rearranged, oncogenic form, appears to encode the receptor for an as yet unidentified ligand. In the mouse embryo, c-ret mRNA is expressed in a subset of the early migrating neural crest cells and their neuronal derivatives, in regions of the central nervous system, and also in the developing excretory system, specifically in the nephric duct, the ureteric bud and the growing tips of the collecting ducts. Newborn mice homozygous for a mutant allele of the c-ret gene, ret-k-, produced through gene targeting in embryonic stem cells, lack the enteric nervous system, and display bilateral renal agenesis or dysgenesis. Thus, the ret protein must play an essential role in the migration, proliferation, differentiation or survival of the enteric neuronal progenitors and their derivatives, as well as in the organogenesis of the kidney, presumably serving as the receptor to a signalling molecule(s) required for development of both the excretory system and the enteric nervous system. We propose to examine the function of the c-ret gene in these developmental processes through a series of studies on the ret-k- mutant mice, as well as through the generation of additional mutant and transgenic strains of mice. In addition, we will attempt to identify and clone the gene encoding the ligand of the c-ret receptor. We propose strategies based on the potential of the ligand to act as a growth factor for cells expressing an exogenous c-ret receptor gene. This work is relevant to our understanding of the relationship between oncogenes and proto-oncogenes, and should also provide new insight into the molecular mechanisms governing the development of the mammalian nervous and excretory systems.