Bilateral NSF/BIO-BBSRC: Regulation of cell size in fission yeast

单元格的大小是如何控制的？细胞的大小千差万别，从微小的细菌到非常大的神经元或原生动物，但特定细胞类型的细胞通常表现出相当恒定的大小。细胞的大小对它们的功能和生计很重要，而且受到严格的监管。然而，总的来说，细胞大小是如何由分子成分决定的，仍然是个谜。有没有尺子可以让细胞决定它有多大？在活跃的细胞分裂中，生长与细胞分裂相协调，从而保持细胞的大小。一种策略是让细胞在经历细胞分裂之前感觉到自己足够大。尽管这种控制已经提出了几十年，但在任何细胞类型中，甚至在细菌和酵母等较简单的情况下，细胞大小感应的机制仍然没有得到适当的理解。我们建议在一种简单的模型细胞类型--分裂酵母中研究细胞大小控制的基本原理。这些细胞因其简单的形状和规则的分裂习性而非常适合这一目的。调节细胞分裂的内部机制对人类来说是保守的，因此在这些简单细胞中的发现通常是相关的。数十年的研究已经确定了调节细胞大小所需的关键分子。然而，这些分子如何被用来感知细胞大小的核心问题仍然知之甚少。我们最近提出了一种新的机制，说明其中一个分子Cdr2是如何用来感知细胞大小的。我们认为，Cdr2探测细胞的表面积，然后在细胞中部聚集成点状结构，称为“节点”。然后，Cdr2可以从这些节点向其他蛋白质报告细胞大小的状态，这些蛋白质告诉细胞分裂。在这项提案中，我们将研究Cdr2如何感知细胞大小，以及它如何向细胞周期机制报告。这项工作涉及数学建模专家和实验者之间的合作，他们将在活的酵母细胞中对荧光标记的蛋白质进行成像。我们的结果将揭示Cdr2和其他分子在细胞中从一个地方到另一个地方的快速移动如何使它能够感觉到细胞的大小。这项工作的重要性在于，它将提供第一批细胞大小感知机制的例子之一。这将对其他细胞如何控制它们的大小产生广泛的影响，并最终为癌症等细胞大小控制发生变化的疾病提供洞察力。

How is the size of a cell controlled? Cells come in vastly different sizes, ranging from tiny bacteria to very large neurons or protozoa, but cells of a given cell type generally display a fairly constant size. The size of cells is important for their function and livelihood, and is tightly regulated. In general, how cell size is specified by molecular components remains, however, mysterious. Are there rulers that allow the cell to determine how big it is? In actively dividing cells, growth is coordinated with cell division so that cell size is maintained. One strategy is for cells to sense that they are big enough before undergoing a cell division. Although such controls have been proposed for decades, the mechanisms for cell size sensing are still not properly understood in any cell type, not even in simpler cases such as bacteria and yeast. We propose to study the fundamentals of cell size control in a simple model cell type, the fission yeast. These cells are ideally suited for this purpose because of their simple shape and regular division habits. The internal machinery that regulates cell division is conserved up to humans, making the findings in these simple cells generally relevant. Decades of research have identified the key molecules needed for cell size regulation. However, the central question of how these molecules are used to sense cell size remains poorly understood. We have recently suggested a new mechanism for how one of these molecules, Cdr2, is used to sense the size of the cell. We propose that Cdr2 probes the surface area of the cell, and then accumulates in dot-like structures in the middle of the cell called "nodes". From these nodes, Cdr2 can then report on the status of cell size to other proteins that tell the cell to divide. In this proposal we will study how Cdr2 senses cell size and how it reports to the cell cycle machinery. This effort involves collaboration between experts in mathematical modelling and experimentalists who will be imaging fluorescently labelled proteins inside living yeast cells. Our results will reveal how the rapid movements of Cdr2 and other molecules from one place to another in the cell allow it to sense cell size. The importance of this work is that it will provide one of the first examples of a cell size sensing mechanism. This will have broad implications into how other cells control their sizes, and ultimately provide insight into diseases such as cancer where cell size controls are altered.