Studies on cell polarity, chemotropism, and cell cycle control

摘要 我们的研究集中在与细胞极性相关的基本问题上。细胞极性描述了这种能力 沿特定轴线在空间上组织其内部成分的细胞。它对细胞迁移至关重要。 (细胞需要生成正面和背面)，也用于开发专门的细胞形状，这些形状 是许多细胞发挥作用所必需的。此外，极性机制的错乱可能有助于 几种疾病，例如，通过使癌症转移。因此，对这些机制的理解， 调控，以及细胞极性的后果既具有根本意义，也具有医学意义。 对细胞极性的研究已经确定了一种进化上古老而保守的核心机制，其核心是 一种称为CDC42的初级极性调节器。然而，许多最有趣的问题仍然存在 悬而未决。为什么大多数细胞只产生一个富含镉的“前沿”，而一些细胞则有更多的 复杂的形状可以指定几个站点作为前台？细胞如何读取它们的环境以 确定它们应该定向极轴的方向？一旦建立了极性，那么 精心策划的精确下游事件集，以使每种细胞类型具有正确的形状？然后，如何 细胞知道它们是什么形状吗？ 我们使用独特易处理的酵母模型系统来研究这些问题，并应用一个组合 尖端显微镜、遗传学和计算建模。我们之前的工作确定了一个积极的 一种反馈机制，解释了CdC42如何集中在极性位置以建立极性 轴心。我们最近关于酵母交配过程中极化的工作，即酵母细胞在空间方向上的反应 信息素的梯度，提出了一种新的范式，称为探索性极化，用于跟踪化学物质 渐变。关于海洋真菌的新发现揭示了新的生活方式，其细胞生物学尚未研究 特色化的。在接下来的5年资助周期中，我们的主要目标是：(I)解决细胞的极性 由细胞周期和信息素信号调节；(Ii)解决关于新的 探索性极化机制，使交配细胞能够找到彼此，以及(Iii)理解如何 海洋真菌在每个细胞周期中产生几个芽，可以将它们的细胞核和细胞器在 不同的花蕾。我们准备在上述问题上取得重大进展，并利用 这些问题的答案提供了远远超出酵母系统的洞察力。

ABSTRACT Our research is focused on fundamental questions related to cell polarity. Cell polarity describes the ability of cells to spatially organize their internal constituents along a specific axis. It is critical for cell migration (where cells need to generate a front and a back), and also for developing specialized cell shapes that are needed for many cells to function. In addition, derangements of the polarity machinery can contribute to several diseases, for example by enabling cancer metastases. Thus, an understanding of the mechanisms, regulation, and consequences of cell polarity is of both fundamental and medical interest. Studies on cell polarity have identified an evolutionarily ancient and conserved core machinery centered on a primary regulator of polarity called Cdc42. However, many of the most interesting questions remain unsolved. How is it that most cells only make a single “front” enriched in Cdc42, but some cells with more complex shapes can specify several sites to act as fronts? How do cells read their environment to determine the direction in which they should orient the polarity axis? Once polarity is established, how is the precise downstream set of events orchestrated to give each cell type the right shape? And then, how do cells know what shape they are? We use the uniquely tractable yeast model system to investigate these questions, and apply a combination of cutting-edge microscopy, genetics, and computational modeling. Our previous work identified a positive feedback mechanism that explains how Cdc42 becomes concentrated at polarity sites to establish a polarity axis. Our recent work on polarization during yeast mating, when yeast cells orient in response to spatial gradients of pheromones, suggests a new paradigm, called Exploratory Polarization, for tracking chemical gradients. And new findings on marine fungi reveal novel lifestyles whose cell biology has yet to be characterized. For the next 5-year grant cycle, our major goals are to (i) address how cell polarity is regulated by cell cycle and pheromone signaling; (ii) address remaining open questions about the new exploratory polarization mechanism that enables mating cells to find each other, and (iii) to understand how marine fungi that make several buds in each cell cycle can partition their nuclei and organelles among the different buds. We are poised to make significant advances on the questions posed above, and to exploit the answers to those questions to provide insights that extend well beyond the yeast system.