Studies of 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 一种名为cdc42的极性“主调节器”。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，提出了一种追踪化学梯度的新范式。而我们的工作是 酵母细胞周期检查点对细胞形状的反应现在建议了一个细胞如何知道什么形状的模型 他们是。基于这些发现，我们准备在提出的问题上取得重大进展 并利用这些问题的答案来提供远远超出酵母的洞察力 系统。

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 “master 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 for tracking chemical gradients. And our work on a yeast cell-cycle checkpoint responsive to cell shape now suggests a model for how cells know what shape they are. Based on these findings, 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.