Spatial, temporal and environmental regulation of early gonadogenesis in C. elegans

 描述(申请人提供)：线虫是研究发育生物学中与人类发育和疾病普遍相关的基本问题的主要模式生物。这项资助的总体目标是研究线虫早期性腺发生的空间、时间和环境调节。线虫的体细胞性腺是研究器官发生的机制和信号事件的一个实验上容易处理的模型。我们将利用强大的基因分析、活体成像、分子操纵和基因组工程方法来实现三个具体目标。其中两个目标与涉及Notch介导的细胞-细胞相互作用的早期性腺发生的空间模式有关。我们将研究随机过程如何产生发育相同的细胞之间的差异，这些细胞通过LIN-12/Notch信号来解决，以及Notch信号需求的不对称是如何产生的，并有助于细胞命运多样化。这些目标的基础生物学与理解干细胞、生物发育和体内组织动态平衡的维持；细胞命运重新编程和潜在的体外治疗应用；以及癌症生物学高度相关。我们所了解的Notch信号和使细胞命运多样化的机制将直接适用于正常发育的其他背景，并且由于Notch活性异常与许多不同的癌症以及发育、免疫和神经疾病有关，拟议的工作对人类健康和疾病具有许多影响。我们还将研究性腺发生过程中细胞和形态发生事件的时间进程是如何在不同的环境条件下被控制的。特别是，我们将研究细胞静止的调节，即细胞退出细胞周期但保持不变的状态 能够重新进入它，在性腺发生的早期。静止是一种基本的细胞特性，它允许干细胞在一段时间内持续存在，而不会失去发育潜力。在第三个目标中，我们将研究时间和环境信息如何控制性腺母细胞进入和退出静止状态。发育过程的环境调控利用了高度保守的胰岛素信号通路，因此研究环境如何影响早期性腺发生可能与包括糖尿病和肥胖症在内的普遍人类疾病有关。总而言之，这项拟议的工作对基本的人类发育生物学以及对人类健康和疾病都有许多影响。通过这些研究我们将获得对发育机制的更深入的理解，这将潜在地适用于开发人类疾病的诊断和治疗工具，这是美国国立卫生研究院的中心任务。

 DESCRIPTION (provided by applicant): C. elegans is a premier model organism for studying basic questions in development biology of general relevance to human development and disease. The overall goal of this grant is to investigate spatial, temporal and environmental regulation of early gonadogenesis in C. elegans. The somatic gonad of C. elegans is an experimentally tractable model for studying mechanisms and signaling events underlying organogenesis. We will use powerful methods for genetic analysis, live imaging, molecular manipulation and genome engineering to achieve three specific aims. Two of the aims are concerned with spatial patterning involving Notch-mediated cell-cell interactions in early gonadogenesis. We will study how stochastic processes generate differences between developmentally equivalent cells that are resolved by LIN-12/Notch signaling, and how an asymmetry in the requirement for Notch signaling is generated and contributes to cell fate diversification. The basic biology of these aims is highly relevant to understanding the cellular dynamics underlying stem cells, organismal development, and the maintenance of tissue homeostasis in vivo; cell fate reprogramming with potential therapeutic applications ex vivo; and cancer biology. What we learn about Notch signaling and mechanisms to diversify cell fate will be directly applicable to other contexts in normal development and, since aberrant Notch activity has been implicated in many different cancers and in developmental, immune, and neurological disorders, the proposed work has many implications for human health and disease. We will also investigate how temporal progression of cellular and morphogenetic events during gonadogenesis is controlled under different environmental conditions. In particular, we will study the regulation of cellular quiescence, a state in which cells have exited the cell cycle but remain capable of re- entering it, in early gonadogenesis. Quiescence is a fundamental cellular property that allows stem cells to persist over time without losing developmental potential. In the third aim, we will study how temporal and environmental information controls the entry into and emergence from quiescence of gonadal blast cells. Environmental regulation of developmental progression utilizes a highly conserved insulin signaling pathway, so studying how the environment impacts early gonadogenesis is potentially relevant to prevalent human diseases including diabetes and obesity. In sum, the proposed work has many implications for basic human developmental biology and for human health and disease. The deeper understanding of developmental mechanism we will achieve through these studies will be potentially applicable for developing diagnostic and therapeutic tools for human disease, a central mission of the NIH.