Abstract
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.
Highlights
Cells that migrate as collectives help establish and organize many tissues and organs in the embryo, yet promote tumor invasion, dissemination and metastasis (Friedl et al, 2012; Friedl and Gilmour, 2009; Wang et al, 2016; Cheung and Ewald, 2016; Scarpa and Mayor, 2016)
To address the role of phosphatases in border cell migration, we carried out a small-scale genetic screen to inhibit selected serine-threonine phosphatases that are expressed during oogenesis using RNAi as well as a protein inhibitor that targets phosphatase 1 (Pp1) catalytic subunits (Table 1; Miskei et al, 2011; Bennett et al, 2003)
Females expressing Nuclear inhibitor of Protein phosphatase 1 (NiPp1) driven by c306-GAL4 did not produce adult progeny when crossed to wild-type males, consistent with infertility and suggesting a role for Pp1 in normal oogenesis (Figure 1—figure supplement 2A)
Summary
Cells that migrate as collectives help establish and organize many tissues and organs in the embryo, yet promote tumor invasion, dissemination and metastasis (Friedl et al, 2012; Friedl and Gilmour, 2009; Wang et al, 2016; Cheung and Ewald, 2016; Scarpa and Mayor, 2016). F-actin and non-muscle myosin II (Myo-II) are enriched at the outer edges of the border cell cluster (Aranjuez et al, 2016; Lucas et al, 2013; Combedazou et al, 2017) Such ‘inside-outside’ polarity contributes to the overall cluster shape, cell-cell organization, and coordinated motility of all border cells (Montell et al, 2012). While progress has been made in understanding the establishment of front-rear polarity, much less is known about how individual border cell behaviors are fine-tuned and adjusted to produce coordinated and cooperative movement of the cluster as an entire unit. We show that Pp1 activity controls multiple collective behaviors of border cells, including timely delamination from the epithelium, collective polarization, cohesion, cell-cell coordination, and migration. Our work identifies Pp1 activity, mediated through distinctive phosphatase complexes such as myosin phosphatase, as a critical molecular regulator of collective cell versus single cell behaviors in a developmentally migrating collective
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