Design principles underlying cell polarity in yeast

描述(由申请人提供)： 建立空间组织是一切生命系统的基本要求。细胞组织中的一个关键元素是细胞极性--一个有向轴的存在，它控制着结构组装、细胞器运输和大分子的定位等过程。几乎所有的细胞类型和不同的生理过程，如细胞分化、细胞运动、神经元生长和免疫反应，都需要细胞的极性。 在发芽酵母的生命周期中，细胞极性对交配和芽的形成是至关重要的。Rho家族的GTP酶CDc42是一个关键的调节因子，极化需要细胞极化的读出和在质膜上特定位置积累活性的CDc42。极化通常发生在对空间和时间线索的反应中。然而，在没有不对称诱导信号的情况下，酵母细胞仍然具有自发极化的能力，尽管方向是随机的。我们假设，细胞的极性是通过两个过程的耦合而产生的：识别不对称线索，以及激活内在的自发机制来打破对称性。 这项研究的主要目的是剖析、拆解和重组酵母发芽途径中的极化机制。我们的方法利用了数学建模和分子遗传学在酵母中的组合优势。这项研究有三个目标：前两个研究了CdC42自发极化的两种机制，一种依赖于细胞骨架，另一种不依赖于细胞骨架。第三个目的是研究通过GTPase级联放大的定位信号如何偏向这些自发的极化机制，以产生单一的、强大的、特定的Cdc42极化位点。

DESCRIPTION (provided by applicant): Establishing spatial organization is a fundamental requirement for all living systems. A critical element in cellular organization is cell polarity - the presence of a directed axis that controls processes such as structural assembly, organelle transport, and localization of macromolecules. Cell polarity is required for nearly all cell types and for diverse physiological processes, such as cell differentiation, cell motility, neuronal growth, and immune responses. In the life cycle of the budding yeast Saccharomyces cerevisiae, cell polarity is critical for mating and bud formation. The Rho-family GTPase Cdc42 is a key regulator and readout of cell polarization and accumulation of activeCdc42 at specific sites on the plasma membrane is required for polarization. Polarization normally occurs in response to spatial and temporal cues. However, in the absence of asymmetric inductive signals, yeast cells still have the ability to spontaneously polarize, albeit in random directions. We hypothesize that cell polarity is brought about through a coupling of two processes: recognition of asymmetric cues, and activation of an intrinsic, spontaneous mechanism to break symmetry. The overarching aim of this investigation is to dissect, disentangle, and reassemble mechanisms of polarization in the yeast budding pathway. Our approach takes advantage of the combined strength of mathematical modeling and molecular genetics in yeast. The proposed research has three goals: The first two investigate two mechanisms of spontaneous polarization of Cdc42, one dependent and the other independent of the cytoskeleton. The third aim examines how localization signals, amplified through a GTPase cascade, bias these spontaneous mechanisms of polarization to yield a single, robust, specified site of Cdc42 polarization.