Functional mapping of Rho GTPase regulatory machineries controlling C. elegans embryonic development

在多细胞生物体中，胚胎的发育依赖于复杂的细胞网络中持续的信息流。信号机制整合多个上游信号的能力在控制细胞行为方面至关重要。然而，人们对这些机制仍然知之甚少。Rho GTP酶与调节其酶活性的蛋白(调节器)一起，是一种信号转导蛋白，涉及广泛的受体下游。因此，它们被认为是细胞信号整合的关键参与者。然而，尽管进行了广泛的努力，单个GTP酶和调控因子的功能表征还不能描述这些基因如何协调它们的功能以整合细胞间信号。为了解决这个问题，我们将使用微小的炉底蠕虫，秀丽线虫作为一个模型系统，来生成控制胚胎发育的Rho特异性调控机制的时空图。为了做到这一点，我们将开发一种整合基因组学方法，包括产生和整合互补的生物信息层。我们的综合方法将产生第一个在多细胞生物体中调节Rho GTP酶的动态模型。该模型随后将被用作更好地理解Rho调节机制与上下游信号模块的相互作用如何指导胚胎发育过程中的细胞信号整合事件的基础。这种模型的构建将有助于全面绘制复杂和动态生物过程中的细胞信号事件图。此外，Rho GTP酶及其调控因子在线虫和人类之间非常保守。它们还与许多人类的病理有关。因此，我们的研究计划将为科学界提供动态模型，这些模型可以用来更好地理解细胞信号机制在正常人类发育过程中的行为以及在病理背景下的行为。

In multicellular organisms, embryonic development is dependent on a continuous flow of information through a complex network of cells. The ability of signaling machinery to integrate multiple upstream signals is critical in the control of cellular behavior. However, these mechanisms are still poorly understood. Rho GTPases together with proteins regulating their enzymatic activity (regulators), are signal transduction proteins involved downstream of a wide range of receptors. They are consequently considered as key players in cell signaling integration. However, despite extensive effort, functional characterization of individual GTPases and regulators has not been able to describe how these genes coordinate their function in order to integrate intercellular signals. To address this issue, we will use the microscopic hearth worm, Caenorhabditis elegans, as a model system to produce a spatiotemporal map of Rho-specific regulatory machineries controlling embryonic development. To do so, we will develop an integrative genomics approach consisting in the generation and integration of complementary layers of biological information. Our integrative approach will produce the first dynamic model of Rho GTPase regulation in a multicellular organism. This model will be subsequently used as a backbone to better understand how interaction of Rho-regulatory machineries with upstream and downstream signaling modules could direct cell signaling integration events during embryonic development. Construction of such a model will significantly contribute to a comprehensive mapping of cell signaling events during complex and dynamic biological processes. Moreover, Rho GTPases and their regulators are extremely well conserved between nematode and human. They are also involved in number of human pathologies. Our research program will consequently provide the scientific community with dynamic models that could be used to better understand the behavior of cell signaling machineries during normal human development as well as in pathological context.