Fascin regulates protrusions and delamination to mediate invasive, collective cell migration in vivo

Abstract

BackgroundThe actin bundling protein Fascin is essential for developmental cell migrations and promotes cancer metastasis. In addition to bundling actin, Fascin has several actin‐independent roles; how these other functions contribute to cell migration remains unclear. Border cell migration during Drosophila oogenesis provides an excellent model to study Fascin's various roles during invasive, collective cell migration.ResultsOn‐time border cell migration during Stage 9 requires Fascin (Drosophila Singed). Fascin functions not only within the migrating border cells, but also within the nurse cells, the substrate for this migration. Fascin genetically interacts with the actin elongation factor Enabled to promote on‐time Stage 9 migration and overexpression of Enabled suppresses the defects seen with loss of Fascin. Loss of Fascin results in increased, shorter and mislocalized protrusions during migration. Additionally, loss of Fascin inhibits border cell delamination and increases E‐Cadherin (Drosophila Shotgun) adhesions on both the border cells and nurse cells.ConclusionsOverall, Fascin promotes on‐time border cell migration during Stage 9 and contributes to multiple aspects of this invasive, collective cell migration, including both protrusion dynamics and delamination. These findings have implications beyond Drosophila, as border cell migration has emerged as a model to study mechanisms mediating cancer metastasis.

Prostaglandins regulate invasive, collective border cell migration

“…We hypothesized that PGs may regulate the actin bundling protein Fascin to control border cell migration. This hypothesis is based on our prior finding that PGs regulate Fascin during S10B to promote actin remodeling ( Groen et al , 2012 ), Fascin is highly expressed in the border cell cluster ( Cant et al , 1994 ), and Fascin is required in both the border cells and the nurse cells for on-time border cell migration ( Lamb et al , 2020 ). To test our hypothesis, we used dominant genetic interaction studies.…”

“…We find that E-cadherin localization and levels appear grossly normal in pxt mutants (Supplemental Figure S4), indicating altered E-cadherin adhesions are not causing the cluster morphology defects. Interestingly, we previously reported that fascin mutant follicles display increased E-cadherin at both the border cell and nurse cell membranes ( Lamb et al , 2020 ). Thus, we hypothesize that Fascin’s function in regulating E-cadherin localization or expression is independent of PG signaling.…”

“…Indeed, PG signaling promotes actin remodeling necessary for late-stage Drosophila follicle morphogenesis by controlling a number of actin-binding proteins, including the actin bundler Fascin ( Groen et al , 2012 ; Spracklen et al , 2014 ; Spracklen et al , 2019 ). Fascin is highly up-regulated in the border cells ( Cant et al , 1994 ) and Fascin is required in both the border cells and the nurse cells for on-time border cell migration during S9 ( Lamb et al , 2020 ). These findings led us to hypothesize PG signaling in the border cells may regulate Fascin and thereby, the actin cytoskeleton.…”

“…As somatic knockdown of Pxt results in delayed migration, we hypothesize PGs regulate the functions of Fascin within the border cells to promote migration. We recently found that Fascin controls protrusions during border cell migration ( Lamb et al , 2020 ). Loss of Fascin results in protrusions extending from all sides of the cluster, and these protrusions are shorter in length and duration.…”

“…These findings suggest that PGs act in both the germline and the somatic cells to regulate border cell migration. As PGs regulate Fascin ( Drosophila singed) to control actin remodeling within the germline ( Groen et al , 2012 ; Spracklen et al , 2019 ), and Fascin is required in both the border cells and nurse cells for on-time border cell migration during S9 ( Lamb et al , 2020 ), we postulated that PGs regulate Fascin to control border cell migration. Indeed, dominant genetic interaction studies reveal that coreduction of Pxt and Fascin phenocopies loss of Pxt, resulting in delayed migration and elongated border cell clusters.…”