CAREER: Cell Specific Analysis of Conserved Spindle Orientation Factors

细胞是组织和有机体的积木，就像积木一样，它们需要正确放置才能形成正确的结构。细胞相对于其周围组织的分裂方向决定了两个子细胞的位置。因此，这个方向有助于组织的形状；例如，定向的细胞分裂与构建有助于组成肺和肾脏的管子有关。位置也有助于细胞类型的多样性；定向细胞分裂有助于解释大脑是如何被一系列不同类型的细胞填充的。该项目利用显微镜和CRISPR介导的基因组编辑方面的最新技术进步，研究模式生物果蝇黑腹果蝇的多种细胞和组织类型的分裂方向。这项工作将解决相对于组织定位细胞分裂的分子机制。更广泛的影响包括研究的内在本质，因为所有多细胞生物体都利用不对称分裂来对组织中的细胞进行分类。其他活动包括促进科学多样性，培训高中、本科生和研究生，以及博士后研究人员。细胞分裂不仅在时间上受到控制，而且在空间上也受到控制。受调控的分裂方向可能会导致不对称性，就像干细胞或祖细胞产生不同细胞命运的子代的情况一样，也与决定组织形状和大小有关。以前的工作表明，分裂方向是在中期决定的，并由一组进化上保守的蛋白质控制。这些蛋白质，包括微管马达动力蛋白，结合在一起产生一个拉力，作用于有丝分裂纺锤体，将其拉成特定的排列。为了正常工作，拉力必须限制在电池外围的特定区域。但是，准确的位置必须根据细胞类型的不同而有所不同。控制拉力局部化的机制尚不清楚，而且似乎是多样化的。研究人员建议首先研究拉力是如何跨细胞类型局部化的。其次，他建议研究一种关键的纺锤体取向因子，称为Mud(在苍蝇中)、NUMA(在脊椎动物中)和Lin-5(在线虫中)，并确定未被预测会促进局部拔出的内源变体的功能。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Cells are building blocks for tissues and organisms, and like building blocks, they need to be correctly placed in order to make the right structure. The direction in which a cell divides with respect to the tissue around it determines the position of the two daughter cells. This direction can therefore contribute to tissue shape; for example, oriented cell divisions are implicated in building the tubes that help comprise the lung and kidneys. Placement can also contribute to cell type diversity; oriented cell divisions help to explain how the brain is populated with a range of different cell types. This project takes advantage of recent technical advances in both microscopy and CRISPR-mediated genome editing to examine division orientation across multiple cell and tissue types in the model organism Drosophila melanogaster. This work will resolve the molecular mechanisms that orient cell divisions with respect to the tissue. The Broader Impact include the intrinsic nature of the research as all multi-cellular organisms utilize asymmetric divisions to sort cells in tissues. Additional activities include promoting diversity in science, the training of high school, undergraduate and graduate students, along with post-doctoral researchers.Cell division is controlled not only in time, but also in space. Regulated division orientation can drive asymmetry, as is often the case with stem or progenitor cells that produce daughters with different cell fates, and is also implicated in determining tissue shape and size. Previous work shows that division orientation is determined at metaphase, and is controlled by an evolutionarily conserved set of proteins. These proteins, which include the microtubule motor dynein, combine to produce a pulling force that acts on the mitotic spindle, drawing it into a particular alignment. In order to function correctly, the pulling force must be restricted to a particular region of the cell periphery. However, the precise location must vary according to the cell type. The mechanisms that control localization of the pulling force are unclear, and appear to be diverse. The investigator proposes firstly to study how the pulling force is localized across cell types. He proposes secondly to study a critical spindle orientation factor called Mud (in flies), NuMA (in vertebrates) and LIN-5 (in nematodes), and to determine the function of endogenous variants that are not predicted to promote localized pulling.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.