ROLE OF RET PROTOONCOGENE IN DEVELOPMENT AND CANCER

Ret原癌基因编码受体酪氨酸激酶（RTK），其在哺乳动物发育和疾病中具有多种作用。RET基因突变与先天性巨结肠相关？的疾病，这是由于缺陷的形成肠神经系统（ENS）的神经嵴祖细胞，而获得性功能突变可导致癌症，包括多发性内分泌瘤。尽管有明确的证据表明RET及其配体参与了这些疾病过程，并且对RET可能激活的下游信号通路进行了广泛的研究，但RET与其他信号系统一起指导ENS正常和异常发育的特定细胞内通路仍有待阐明。在这里，我们专注于RET调节神经嵴细胞的增殖，迁移，存活和分化的机制在发展中的肠道。我们的方法广泛使用敲入小鼠模型，以及器官和细胞培养系统，以检查肠神经嵴细胞中的基因修饰的RET受体的体内功能。我们要解决的问题是（1）RET作为促凋亡因子的可能作用，它可以通过涉及RET胞内结构域的切割的机制促进细胞死亡，以及这种功能在正常胚胎发生和成年动物肿瘤抑制中的重要性;（2）RET和内皮素受体β信号通路相互作用以控制ENS的正常组织发生的机制，以及PKA和其他丝氨酸/苏氨酸激酶在这些相互作用中的可能作用;以及（3）两种主要RET同种型RET 9和RET 51的不同信号传导能力的分子基础，它们在支持正常ENS发育的能力上不同。这些研究不仅将促进我们对这种RTK在肠神经系统发育过程中如何发挥作用的理解，而且将提供对下游信号传导途径的深入了解，这些途径可能是治疗RET相关癌症的干预目标。

The Ret proto-oncogene encodes a receptor tyrosine kinase (RTK) which has diverse roles in mammalian development and disease. Loss-of-function RET mutations are associated with Hirschsprung?s disease, which results from defects in the formation of the enteric nervous system (ENS) from neural crest progenitors, while gain-of-function mutations can cause cancers including Multiple Endocrine Neoplasia. Despite clear evidence implicating RET and its ligands in these disease processes, and extensive studies of the downstream signaling pathways that can potentially be activated by RET, the specific intracellular pathways through which RET, together with other signaling systems, directs the normal and abnormal development of the ENS remains to be elucidated. Here we focus on the mechanism by which RET regulates the proliferation, migration, survival and differentiation of neural crest cells in the developing gut. Our approach makes extensive use of knock-in mouse models, as well as organ and cell culture systems, to examine the in vivo functions of the genetically modified RET receptors in enteric neural crest cells. The questions we address are (1) the possible role of RET as a pro-apoptotic factor, which can promote cell death through a mechanism involving cleavage of the RET intracellular domain, and the importance of this function in normal embryogenesis and in tumor suppression in the adult animal; (2) the mechanisms by which RET and the endothelin receptor-beta signaling pathways interact to control the normal histogenesis of the ENS, and the possible role of PKA and other serine/threonine kinases in these interactions; and (3) the molecular basis for the distinct signaling abilities of the two major RET isoforms, RET9 and RET51, which differ in their capacity to support normal ENS development. These studies will not only advance our understanding of how this RTK functions during development of the enteric nervous system, but will provide insight into the downstream signaling pathways that might be targets for intervention in the treatment of Ret-related cancers.