ROLE OF RET PROTOONCOGENE IN DEVELOPMENT AND CANCER

Ret原癌基因编码一种受体酪氨酸激酶(RTK)，在哺乳动物的发育和疾病中起着不同的作用。功能缺失的RET突变与先天性巨结肠-S病有关，该病是由神经脊祖细胞的肠道神经系统(ENS)形成缺陷引起的，而功能获得突变可导致包括多发性内分泌肿瘤在内的癌症。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正常和异常发育的具体细胞内途径仍有待阐明。在这里，我们重点介绍RET在发育中的肠道中调节神经脊细胞的增殖、迁移、存活和分化的机制。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，以检查肠道神经脊细胞中转基因RET受体的体内功能。我们解决的问题包括：(1)RET作为促凋亡因子的可能作用，它可以通过裂解RET胞内域的机制促进细胞死亡，以及这一功能在成年动物正常胚胎发育和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)两种主要的RET亚型RET9和RET51具有不同信号能力的分子基础，它们支持正常的ENS发育。这些研究不仅将促进我们对RTK在肠道神经系统发育过程中如何发挥作用的理解，还将为我们深入了解下游信号通路，这些信号通路可能是干预Ret相关癌症治疗的靶点。

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.