Control of Vulval Differentiation in C. elegans

描述(由申请人提供)：发育决定由多个调控途径的联合作用控制。调控的一个关键方面是控制特定发育程序的开始时间，使细胞能够对其他信号做出反应。我们的目标是了解几个基因调控发育时机的遗传和生化机制，并了解调控途径与特定细胞事件(如细胞分裂和分化)之间的联系。在这项资助下的研究以线虫外阴诱导作为模型系统来研究多个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控外阴细胞分裂时间的基因。其中，LIN-66抑制关键的时间调控因子LIN-28的表达，AIN-1与MicroRNA诱导的复合体(Mirics)的ALG-1、DICER和microRNA结合，并将ALG-1靶向特定的细胞质靶点。作用于Ras-MAPKinase下游的一个转录因子Lin-31也参与了时间调控。我们将进行一系列的分子和遗传学实验，以了解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。通过识别与AIN-1相关的miRNAs及其靶点，我们将确定AIN-1是否只与其功能的miRNAs子集相关，以及了解这些靶点所携带的这些特定功能。我们还计划研究与AIN-1结构和功能相似的AIN-2以及另外两个基因的功能。最后，我们将寻找LIN-31的靶点，以了解哪些因素在时序调节和介导RAS信号转导中执行LIN-31的调节作用。MicroRNA的功能和RAS信号在蠕虫和人类之间是保守的，并参与了许多人类发育过程和疾病，如癌症。对线虫的研究对相关领域的研究产生了巨大的影响。这项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.