ROLE OF RET PROTOONCOGENE IN DEVELOPMENT AND CANCER

RET原癌基因编码一种受体酪氨酸激酶，其作用是 神经胶质细胞系源性神经营养因子受体的一个组成部分 因子(GDNF)和相关因子神经突蛋白(NTN)。对中国传统文化的分析与思考 携带RET和GDNF零突变的小鼠已经确定RET 信号是肠道和肠道正常发育所必需的 交感神经系统和排泄系统。在人类身上， RET基因突变与先天性肠无神经节细胞增多症相关 (先天性巨结肠)和遗传性癌症综合征。多重 内分泌肿瘤(男性)2A型和2B型。在建议的研究中，我们 继续我们对RET基因在 神经系统的发育和癌症。而RET基因缺失的小鼠 我们所产生的将继续是许多 这些研究，我们还将产生几种新类型的突变小鼠 RET基因的特定改变。一些突变会改变 与特定细胞内信号相互作用的单个残基 分子，使我们能够剖析特定下游分子的作用 RET不同发育功能中的信号通路。其他 突变小鼠将携带RET等位基因，其氨基酸替换在 人类MEN2A或MEN2B，代表可能提供新的 洞察这些疾病的病因学。我们还将调查 酵母双杂交系统鉴定MEN2B的分子基础 与野生型和突变型激酶相互作用差异的蛋白质 域名。在四项研究的基础上， 肠道神经系统(ENS)，我们将使用器官型培养系统 为胚胎肠道检测GDNF和NTN在细胞中的作用 在ENS开发过程中的迁移。可能扮演的不同角色 两个RET共受体GFRpha-1或GFRpha-2在心脏发育中的作用 神经内分泌系统以及神经系统的其他部分将被调查 通过培育突变小鼠。最后，我们将考察该角色 Eph受体酪氨酸激酶及其在ENS模式中的位置。

The RET proto-oncogene encodes a receptor-tyrosine kinase that serves as a component of the receptor for the glial cell-line-derived neurotrophic factor (GDNF) and the related factor neurturin (NTN). The analysis of the mice carrying RET and GDNF null mutations has established that RET signaling is required for the normal development of the enteric and sympathetic nervous systems as well as the excretory system. In humans, RET mutations are associated with congenital intestinal aganglionosis (Hirschsprung's disease) and the inherited cancer syndromes. Multiple Endocrine Neoplasia (MEN) Type 2A and 2B. In the proposed studies, we continue our investigations of the roles of the RET gene in the development of the nervous system and in cancer. While the RET-null mice that we have generated will continue to be an important tool in many of these studies, we will also generate several new types of mutant mice with specific alterations in the RET gene. Some of the mutations will alter individual residues that interact with specific intracellular signaling molecules, allowing us to dissect the roles of specific downstream signaling pathways in the diverse developmental functions of RET. Other mutant mice will carry RET alleles with amino acid substitutions found in human MEN2A or MEN2B, representing animal models that may provide new insight into the etiology of these diseases. We will also investigate the molecular basis the MEN2B by using the yeast-two hybrid system to identify proteins that interact differentially with the wild type and mutant kinase domains. In a continuation o four studies on the development of the enteric nervous system (ENS), we will use an organotypic culture system for the embryonic gut to examine the roles of the GDNF and NTN in cell migration during ENS development. The potentially different roles of the two RET co-receptors GFRalpha-1 or GFRalpha-2 in the development of the ENS, as well as other parts of the nervous system, will be investigated through the production of mutant mice. Finally, we will examine the role of Eph receptor tyrosine kinases and their lands in patterning of the ENS.