CAREER: Cell Specific Analysis of Conserved Spindle Orientation Factors

细胞是组织和生物体的基石，就像基石一样，它们需要被正确放置才能形成正确的结构。细胞相对于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形状；例如，定向细胞分裂涉及到构建帮助组成肺和肾的管道。放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由一系列不同类型的细胞组成的。该项目利用显微镜和crispr介导的基因组编辑的最新技术进步来检查模式生物果蝇（Drosophila melanogaster）中多种细胞和组织类型的分裂方向。这项工作将解决定向细胞分裂相对于组织的分子机制。更广泛的影响包括研究的内在性质，因为所有多细胞生物都利用不对称分裂来分类组织中的细胞。其他活动包括促进科学多样性，培养高中生、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控制，而且在空间上也受控制。受调节的分裂方向可以驱动不对称，就像干细胞或祖细胞产生具有不同细胞命运的子细胞的情况一样，并且还涉及决定组织形状和大小。先前的研究表明，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，结合起来产生一种拉力，作用于有丝分裂纺锤体，把它拉到一个特定的位置。为了正确发挥作用，拉力必须限制在细胞外围的特定区域。但是，精确位置必须根据单元格类型而变化。控制拉力定位的机制尚不清楚，似乎是多种多样的。研究者首先提出研究拉力如何在细胞类型之间定位。其次，他建议研究一种关键的纺锤体取向因子，称为Mud（果蝇），NuMA（脊椎动物）和LIN-5（线虫），并确定内源性变异的功能，这些变异不被预测会促进局部拉力。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.