Control of Vulval Differentiation in C. elegans

描述（由申请人提供）：发育决定是由多种调控途径的联合作用控制的。调控的一个关键方面是控制特定发育程序开始的时间，使细胞有能力对其他信号作出反应。我们的目标是了解几个基因调节发育时间的遗传和生化机制，并了解调节途径与特定细胞事件（如细胞分裂和分化）之间的联系。这项资助下的研究使用秀丽隐杆线虫外阴诱导作为模型系统来研究多种途径的功能和相互作用，包括Ras-MAP激酶途径。最近，通过寻找Ras信号下游的基因，我们已经确定了四个参与调节外阴细胞分裂时间的基因。其中，LIN-66抑制关键定时调节因子LIN-28的表达，AIN-1结合ALG-1、Dicer和microRNA诱导复合物（miRICS）的microRNA，将ALG-1靶向特异性细胞质病灶。Ras-MAPkinase下游的转录因子LIN-31也参与了时间调节。我们将开展一系列分子和遗传学实验，了解LIN-66如何调节lin-28的表达，以及AIN-1为miRISCs提供了哪些生化特性。通过鉴定与ai -1相关的mirna及其靶标，我们将确定ai -1是否仅与mirna的一部分功能相关，并了解这些靶标所携带的这些特定功能。我们还计划研究与AIN-1具有结构和功能相似性的AIN-2以及其他两个基因的功能。最后，我们将寻找LIN-31的靶点，以了解LIN-31在时间调控和介导的Ras信号传导中发挥调控作用的因素。microRNA功能和Ras信号在蠕虫和人类之间是保守的，并参与许多人类发育过程和疾病，如癌症。秀丽隐杆线虫的研究对相关领域的研究产生了巨大的影响。拟议的研究旨在为这些新发现的基因所涉及的细胞过程提供新的见解。

DESCRIPTION (provided by applicant): Developmental decisions are controlled by the combined action of multiple regulatory pathways. One critical aspect of regulation is the controlled timing of the onset of specific developmental programs that render cells competent for responding to other signals. Our goal is to understand the genetic and biochemical mechanisms by which several genes regulate developmental timing and to understand the link between the regulatory pathway and specific cellular events such as cell divisions and differentiations. Research under this grant has used C. elegans vulval induction as a model system to investigate the functions and interactions of multiple pathways, including the Ras-MAP kinase pathway. Recently, by searching for genes acting downstream of Ras signaling, we have identified four genes that are involved in regulating the timing of vulval cell divisions. Among them, LIN-66 represses the expression of a key timing regulator LIN-28, and AIN-1 binds to ALG-1, Dicer and microRNA of the microRNA induced complexes (miRICS) and targets ALG-1 to specific cytoplasmic foci. A transcription factor LIN-31 that acts downstream of Ras-MAPkinase is also involved in timing regulation. We will carry out a series molecular and genetic experiments to understand how LIN-66 regulates lin-28 expression and what biochemical properties AIN-1 provides to miRISCs. Through identifying the miRNAs and their targets associated with AIN-1, we will determine if AIN-1 is associated with only a subset of miRNAs for their functions, as well as learning about these specific functions carried by these targets. We also plan to study the functions of AIN-2, which has structural and functional similarities to AIN-1, as well as two other genes. Finally, we will search for targets of LIN-31 to learn about what factors execute the regulatory role of LIN-31 in timing regulatory and in mediated Ras signaling. microRNA functions and Ras signaling are conserved between worms and human, and are involved in many human developmental processes and diseases, such as cancers. Studies in C. elegans have made a huge impact on the research in related fields. The proposed research intends to provide new insights into cellular processes involved in these newly identified genes.