Table3_Specific prostaglandins are produced in the migratory cells and the surrounding substrate to promote Drosophila border cell migration.XLSX

Introduction: A key regulator of collective cell migration is prostaglandin (PG) signaling. However, it remains largely unclear whether PGs act within the migratory cells or their microenvironment to promote migration. Here we use Drosophila border cell migration as a model to uncover the cell-specific roles of two PGs in collective migration. The border cells undergo a collective and invasive migration between the nurse cells; thus, the nurse cells are the substrate and microenvironment for the border cells. Prior work found PG signaling is required for on-time border cell migration and cluster cohesion.
Methods: Confocal microscopy and quantitative image analyses of available mutant alleles and RNAi lines were used to define the roles of the PGE2 and PGF2α synthases in border cell migration.
Results: We find that the PGE2 synthase cPGES is required in the substrate, while the PGF2α synthase Akr1B is required in the border cells for on-time migration. Akr1B acts in both the border cells and their substrate to regulate cluster cohesion. One means by which Akr1B may regulate border cell migration and/or cluster cohesion is by promoting integrin-based adhesions. Additionally, Akr1B limits myosin activity, and thereby cellular stiffness, in the border cells, whereas cPGES limits myosin activity in both the border cells and their substrate. Decreasing myosin activity overcomes the migration delays in both akr1B and cPGES mutants, indicating the changes in cellular stiffness contribute to the migration defects.
Discussion: Together these data reveal that two PGs, PGE2 and PGF2α, produced in different locations, play key roles in promoting border cell migration. These PGs likely have similar migratory versus microenvironment roles in other collective cell migrations.

引言：集体细胞迁移的关键调控因子是前列腺素（prostaglandin，PG）信号通路。然而目前尚不清楚前列腺素（PG）是在迁移细胞自身还是其微环境中发挥作用以促进细胞迁移。本研究以果蝇（Drosophila）边界细胞迁移为模型，揭示了两种前列腺素（PG）在集体迁移中的细胞特异性功能。边界细胞会在滋养细胞之间进行集体侵袭性迁移，因此滋养细胞是边界细胞的迁移底物与微环境。已有研究表明，PG信号通路对于边界细胞的按时迁移以及细胞簇黏附完整性是必需的。
方法：本研究通过共聚焦显微镜成像与定量图像分析，结合已有的突变等位基因与RNA干扰（RNAi）品系，明确了前列腺素E2（PGE2）合酶与前列腺素F2α（PGF2α）合酶在边界细胞迁移中的功能。
结果：研究发现，PGE2合酶cPGES在迁移底物中发挥必需作用，而PGF2α合酶Akr1B则需在边界细胞中表达以保障迁移按时进行。Akr1B同时在边界细胞及其迁移底物中发挥作用，以调控细胞簇的黏附完整性。Akr1B调控边界细胞迁移及/或细胞簇黏附的潜在机制之一是促进基于整合素的细胞黏附。此外，Akr1B可在边界细胞中抑制肌球蛋白活性，进而降低细胞刚度；而cPGES则在边界细胞及其迁移底物中均可抑制肌球蛋白活性。降低肌球蛋白活性可缓解akr1B与cPGES突变体中的迁移延迟表型，表明细胞刚度的改变是导致迁移缺陷的关键原因。
讨论：综上，本研究数据表明，两种前列腺素——PGE2与PGF2α——在不同部位产生，在促进边界细胞迁移中发挥关键作用。这类前列腺素在其他集体细胞迁移过程中，可能也具有类似的细胞自主迁移调控与微环境调控功能。