Phosphatase Control of Collective Cell Migration during Development

细胞移动并迁移到发育中动物体内的新位置，这是器官正确形成和功能的重要一步。这项拟议中的研究使用一种简单的遗传模型，即果蝇，来研究细胞如何作为有组织的群体在动物体内运动。这些研究的总体目标是确定在细胞运动过程中保持细胞在一起的基本机制，这是一个知之甚少的过程。这些研究的结果有望揭示细胞在动物发育过程中迁移到组织和器官的方式。拟议项目的一个主要影响是培训学生和鼓励代表性不足的群体从事科学密集型职业。由于易于使用和可用的遗传工具，这些果蝇模型的研究非常适合学生的培训。McDonald实验室有着培养不同背景的本科生和研究生的历史，并将在拟议的研究中继续这样做。研究人员将专门从目前提供有限研究机会的三所当地机构招募女性和代表性不足的少数民族本科生。该项目还包括在拟议研究的基础上，向主要由代表性不足的少数群体组成的当地小学和高中开展几项外联工作。这些活动将向学生介绍遗传学和动物细胞和发育生物学的研究，并鼓励他们追求科学和技术事业。在整个发育过程中，细胞经常成群移动，形成，塑造和重塑组织和器官。这种“集体”迁移的细胞彼此强烈粘附，但也协调整个群体作为一个单一单位的运动。尽管它们对发育至关重要，但细胞如何集体迁移而不是单独迁移仍然缺乏特征。果蝇的边缘细胞代表了一个遗传上可访问的模型，用于发现集体细胞运动背后的基本调控途径。磷酸化和去磷酸化的动态循环调节参与个体和集体细胞迁移的细胞信号传导途径和物理/细胞骨架动力学。虽然蛋白激酶的功能已得到充分证实，但对蛋白磷酸酶的作用知之甚少。新的初步数据表明，蛋白磷酸酶活性是一个意想不到的控制器的集体凝聚力和迁移的边缘细胞。磷酸酶活性受到抑制的边缘细胞聚集，从主群中脱落，无法完成迁移。这个建议的中心假设是，不同的磷酸酶复合物保持一个集体的迁移模式，通过动态调节可识别的基板。该项目结合了遗传学、活体成像、细胞生物学和生物化学方法，以确定哪些磷酸酶复合物调节集体边界细胞迁移。此外，这些研究将确定磷酸酶靶蛋白负责集体凝聚力和迁移的边缘细胞。由于共同的机制是不同的集体细胞迁移过程的基础，利用强大的边缘细胞模型的研究将揭示新的蛋白磷酸酶调控的细胞和分子途径。总之，这将极大地推进器官如何形成的知识，并在多细胞生物体的发展过程中被集体重塑。

Cells move and migrate to new locations in the bodies of developing animals, an important step for the correct formation and function of organs. The proposed research uses a simple genetic model, the fruit fly, to investigate how cells move as organized groups within the animal. The overall goal of these studies is to identify fundamental mechanisms that keep cells together during cell movement, a poorly understood process. Results from these studies are expected to shed light on the way that cells migrate to populate tissues and organs during animal development. A major impact of the proposed project is the training of students and encouragement of underrepresented groups to pursue scientific-intensive careers. Because of the ease of use and available genetic tools, these studies with the fruit fly model are ideally suited for the training of students. The McDonald lab has a history of training undergraduate and graduate students from diverse backgrounds, and will continue to do so in the proposed studies. The investigator will specifically recruit female and underrepresented minority undergraduate students from three local institutions that currently offer limited research opportunities. The project also includes several outreach efforts, based on the proposed research, to a local grade school and high school comprised mainly of underrepresented minorities. These activities together will introduce students to research in genetics and animal cell and developmental biology and encourage them to pursue scientific and technical careers.Throughout development cells frequently move in groups to form, shape and remodel tissues and organs. Such "collectively" migrating cells adhere strongly to one another but also coordinate movement of the whole group as a single unit. Despite their crucial importance to development, how cells migrate collectively rather than individually remains poorly characterized. Drosophila border cells represent a genetically accessible model for the discovery of fundamental regulatory pathways that underlie collective cell movement. Dynamic cycles of phosphorylation and dephosphorylation regulate the cellular signaling pathways and physical/cytoskeletal dynamics involved in individual and collective cell migration. While the functions of protein kinases are well established, much less is known about the roles of protein phosphatases. Novel preliminary data indicate that protein phosphatase activity is an unanticipated controller of collective cohesion and migration of border cells. Border cells in which phosphatase activity is inhibited round up, break off from the main group and are unable to complete their migration. The central hypothesis of this proposal is that distinct phosphatase complexes maintain a collective mode of migration through dynamic regulation of identifiable substrates. The proposed project combines genetic, live imaging, cell biology and biochemical approaches to determine which phosphatase complexes regulate collective border cell migration. Moreover, these studies will identify phosphatase target proteins responsible for the collective cohesion and migration of border cells. As common mechanisms underlie different collective cell migration processes, the proposed studies utilizing the powerful border cell model will uncover new cellular and molecular pathways regulated by protein phosphatases. Together, this will critically advance knowledge of how organs form and are remodeled by collectives during development of multicellular organisms.