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ABSTRACT Migratory cells – either individually or in cohesive groups – are critical for spatiotemporally regulated processes such as embryonic development and wound healing. Their dysregulation is the underlying cause of formidable health problems such as congenital abnormalities and metastatic cancers. Border cell behavior during Drosophila oogenesis provides an effective model to study temporally regulated, collective cell migration in vivo. Developmental timing in flies is primarily controlled by the steroid hormone ecdysone, which acts through a well-conserved, nuclear hormone receptor complex. Ecdysone signaling determines the timing of border cell migration, but the molecular mechanisms governing this remain obscure. We found that border cell clusters expressing a dominant-negative form of ecdysone receptor extended ineffective protrusions. Additionally, these clusters had aberrant spatial distributions of E-cadherin (E-cad), apical domain markers and activated myosin that did not overlap. Remediating their expression or activity individually in clusters mutant for ecdysone signaling did not restore proper migration. We propose that ecdysone signaling synchronizes the functional distribution of E-cadherin, atypical protein kinase C (aPKC), Discs large (Dlg1) and activated myosin post-transcriptionally to coordinate adhesion, polarity and contractility and temporally control collective cell migration.
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Two phases for centripetal migration of Drosophila melanogaster follicle cells: initial ingression followed by epithelial migration
ABSTRACT During Drosophila oogenesis, somatic follicle cells (FCs) differentiate to secrete components of the eggshell. Before secretion, the epithelium reorganizes to shape eggshell specializations, including border FC collective cell migration and later dorsal formation. These FC movements provide valuable insights into collective cell migration. However, little is known about centripetal migration, which encloses the oocyte after secretion has begun. Centripetal migration begins with apical extension of a few FCs that move away from the basement membrane to invade between germ cells. We define a timeline of reproducible milestones, using time-lapse imaging of egg chamber explants. Inward migration occurs in two phases. First, leading centripetal FCs ingress, extending apically over the anterior oocyte, and constricting basally. Second, following FCs move collectively toward the anterior, then around the corner to move inward with minimal change in aspect ratio. E-cadherin was required in leading centripetal FCs for their normal ingression, assessed with homozygous shotgun mutant or RNAi knockdown clones; ingression was influenced non-autonomously by mutant following FCs. This work establishes centripetal migration as an accessible model for biphasic E-cadherin-adhesion-mediated collective migration.
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- Award ID(s):
- 1355091
- PAR ID:
- 10585456
- Publisher / Repository:
- Company of Biologists
- Date Published:
- Journal Name:
- Development
- Volume:
- 150
- Issue:
- 6
- ISSN:
- 0950-1991
- Page Range / eLocation ID:
- 200492
- Subject(s) / Keyword(s):
- Collective cell migration, Ingression, Epithelial organization, Oogenesis, Centripetal migration, Cadherin adhesion
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Collective cell migration is central to many developmental and pathological processes. However, the mechanisms that keep cell collectives together and coordinate movement of multiple cells are poorly understood. Using the Drosophila border cell migration model, we find that Protein phosphatase 1 (Pp1) activity controls collective cell cohesion and migration. Inhibition of Pp1 causes border cells to round up, dissociate, and move as single cells with altered motility. We present evidence that Pp1 promotes proper levels of cadherin-catenin complex proteins at cell-cell junctions within the cluster to keep border cells together. Pp1 further restricts actomyosin contractility to the cluster periphery rather than at individual internal border cell contacts. We show that the myosin phosphatase Pp1 complex, which inhibits non-muscle myosin-II (Myo-II) activity, coordinates border cell shape and cluster cohesion. Given the high conservation of Pp1 complexes, this study identifies Pp1 as a major regulator of collective versus single cell migration.more » « less
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Abstract BackgroundCollective cell migration underlies many essential processes, including sculpting organs during embryogenesis, wound healing in the adult, and metastasis of cancer cells. At mid-oogenesis,Drosophilaborder cells undergo collective migration. Border cells round up into a small group at the pre-migration stage, detach from the epithelium and undergo a dynamic and highly regulated migration at the mid-migration stage, and stop at the oocyte, their final destination, at the post-migration stage. While specific genes that promote cell signaling, polarization of the cluster, formation of protrusions, and cell-cell adhesion are known to regulate border cell migration, there may be additional genes that promote these distinct active phases of border cell migration. Therefore, we sought to identify genes whose expression patterns changed during border cell migration. ResultsWe performed RNA-sequencing on border cells isolated at pre-, mid-, and post-migration stages. We report that 1,729 transcripts, in nine co-expression gene clusters, are temporally and differentially expressed across the three migration stages. Gene ontology analyses and constructed protein-protein interaction networks identified genes expected to function in collective migration, such as regulators of the cytoskeleton, adhesion, and tissue morphogenesis, but also uncovered a notable enrichment of genes involved in immune signaling, ribosome biogenesis, and stress responses. Finally, we validated the in vivo expression and function of a subset of identified genes in border cells. ConclusionsOverall, our results identified differentially and temporally expressed genetic networks that may facilitate the efficient development and migration of border cells. The genes identified here represent a wealth of new candidates to investigate the molecular nature of dynamic collective cell migrations in developing tissues.more » « less
- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1242/dev.200492
