DEVELOPMENTAL FUNCTION OF THE C-RET PROTO-ONCOGENE

这个项目的目的是阐明人的发育功能 原癌基因c-ret编码的受体酪氨酸激酶(RTK)。 RTK，其中许多在重排或病毒感染后可作为癌基因 转导，通常作为细胞受体的各种 在发育中具有重要作用的生长和分化因子。 C-ret基因，首先以其重排的致癌形式被发现， 似乎编码了一种尚未确定的配体的受体。在 在小鼠胚胎中，c-ret mRNA在早期迁移的亚群中表达 神经脊细胞及其神经元衍生物，位于 中枢神经系统，以及发育中的排泄系统， 特别是在肾管、输尿管芽和生长的尖端 收集管道的一部分。新生小鼠纯合子突变的等位基因 在胚胎干细胞中通过基因打靶产生的c-ret基因ret-k- 细胞，缺乏肠道神经系统，表现为双侧肾 发育不全或发育不良。因此，ret蛋白必须发挥重要的作用。 在生物的迁移、增殖、分化或生存中的作用 肠神经前体细胞及其衍生物，以及在 肾脏的器官发生，推测为肾脏的受体。 两种排泄物发育所需的信号分子(S) 系统和肠道神经系统。我们建议研究 C-ret基因在这些发育过程中的作用 对ret-k-突变小鼠的一系列研究，以及通过 额外的突变和转基因小鼠品系的产生。在……里面 此外，我们还将尝试鉴定和克隆编码 C-ret受体的配体。我们提出的策略是基于 该配体作为细胞生长因子表达的潜力 外源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， 也应该为分子机制提供新的见解 支配哺乳动物的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.