Prostaglandins regulate mechanotransduction to the nucleus

Prostaglandins (PGs) are lipid signals that play critical roles in physiology, including regulating pain and inflammation, reproduction, and cancer. However, the cellular mechanisms of PG action remain poorly understood. PGs are synthesized downstream of cyclooxygenase (COX) enzymes. In Drosophila, there is one COX‐like enzyme Pxt. Loss of PG synthesis in both mammals and flies results in female sterility. Specifically, in flies the loss of Pxt causes numerous defects in oogenesis, i.e. follicle development. One mechanism whereby PGs mediate follicle development is by regulating actin cytoskeletal remodeling necessary for both cell migration, and cellular and follicular morphogenesis. Here we focus on the role of PGs in regulating the invasive and collective migration of somatic cells termed border cells. The border cells delaminate from the epithelium surrounding the follicle, invade between the germline‐derived nurse or support cells, and migrate to the dorsal anterior of the oocyte. Loss of PGs results in both delayed migration, and cluster elongation and disruption. Invasive migration is highly dependent on the ability of the cells to respond to mechanical force. Substrate stiffness is sensed by cell surface receptors, these receptors transmit the mechanical information to the cytoskeleton, and the cytoskeleton interacts with the Linker of the Nucleoskeleton and Cytoskeleton (LINC) Complex on the nuclear envelope to convey that information to the nucleus. The nucleus then responds by altering its shape and/or stiffness. Our findings support that model that PGs regulate border cell migration by controlling the actin binding protein Fascin, and that Fascin, in turn, regulates the activity of the LINC Complex to mediate the changes in nuclear position and shape needed for invasive cell migration. The model is supported by the following findings. First, PGs regulate Fascin later in oogenesis to control actin remodeling necessary for follicle morphogenesis. Second, Fascin is highly expressed in the border cells and regulates invasive cell migration in other systems. Third, Fascin localizes to the nuclear periphery, and this localization requires both PG signaling and a functional LINC Complex. Finally, loss of either Fascin or the LINC Complex results in pxt ‐like border cell migration defects. These studies are expected to establish the molecular mechanisms whereby PG signaling regulates mechanical signaling to the nucleus to control nuclear position and shape changes necessary for invasive migration. Such findings are applicable to other 3D cell migrations, including those occurring during development and in the context of cancer. Support or Funding Information NIH/NIGMS R01GM116885