Abstract
Individual cells detach from cohesive ensembles during development and can inappropriately separate in disease. Although much is known about how cells separate from epithelia, it remains unclear how cells disperse from clusters lacking apical–basal polarity, a hallmark of advanced epithelial cancers. Here, using live imaging of the developmental migration program of Drosophila primordial germ cells (PGCs), we show that cluster dispersal is accomplished by stabilizing and orienting migratory forces. PGCs utilize a G protein coupled receptor (GPCR), Tre1, to guide front-back migratory polarity radially from the cluster toward the endoderm. Posteriorly positioned myosin-dependent contractile forces pull on cell–cell contacts until cells release. Tre1 mutant cells migrate randomly with transient enrichment of the force machinery but fail to separate, indicating a temporal contractile force threshold for detachment. E-cadherin is retained on the cell surface during cell separation and augmenting cell–cell adhesion does not impede detachment. Notably, coordinated migration improves cluster dispersal efficiency by stabilizing cell–cell interfaces and facilitating symmetric pulling. We demonstrate that guidance of inherent migratory forces is sufficient to disperse cell clusters under physiological settings and present a paradigm for how such events could occur across development and disease.
Highlights
Individual cells detach from cohesive ensembles during development and can inappropriately separate in disease
In contrast to what is known about epithelial delamination, little is known about how actomyosin contractility contributes to cluster dispersal in vivo, despite relevance to understanding how cells detach from cell masses with disrupted apical–basal polarity, a hallmark of advanced epithelial cancers[16]
WT primordial germ cells (PGCs) were initially tightly clustered within the endoderm cavity in a rosette configuration[12], with higher levels of F-actin assembly and/or contraction arising in cell interfaces abutting the rosette center (Fig. 1a and Supplementary Movie 1)
Summary
Individual cells detach from cohesive ensembles during development and can inappropriately separate in disease. Much is known about how cells separate from epithelia, it remains unclear how cells disperse from clusters lacking apical–basal polarity, a hallmark of advanced epithelial cancers. Using live imaging of the developmental migration program of Drosophila primordial germ cells (PGCs), we show that cluster dispersal is accomplished by stabilizing and orienting migratory forces. Aside from an epithelium, individual cells can detach from cell clusters lacking apical–basal polarity during developmental migration. The stable apical–basal polarity present in an epithelium, which presents an existing template for contractile forces to mediate delamination, is replaced by a dynamic front–back polarity in a cluster This polarity can be labile and it is unclear how forces in this context are directed toward separation. Known autonomous proteins required for PGC cluster dispersal are the orphan G-protein-coupled receptor (GPCR), Tre[1] (Fig. 1b) and its associated Gβγ subunit, consisting of Gβ13F and Gγ1, as well as the small Rho GTPase, RhoA12,20,22, suggesting the involvement of contractile forces
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