scholarly journals Rap1 GTPase promotes coordinated collective cell migration in vivo

2018 ◽  
Vol 29 (22) ◽  
pp. 2656-2673 ◽  
Author(s):  
Ketki Sawant ◽  
Yujun Chen ◽  
Nirupama Kotian ◽  
Kevin M. Preuss ◽  
Jocelyn A. McDonald
Keyword(s):  
Small Gtpase ◽  
Cell Junctions ◽  
Cell Group ◽  
Specific Cell ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Collective Migration ◽  
Border Cell ◽  
Unit Cells

During development and in cancer, cells often move together in small to large collectives. To move as a unit, cells within collectives need to stay coupled together and coordinate their motility. How cell collectives remain interconnected and migratory, especially when moving through in vivo environments, is not well understood. The genetically tractable border cell group undergoes a highly polarized and cohesive cluster-type migration in the Drosophila ovary. Here we report that the small GTPase Rap1, through activation by PDZ-GEF, regulates border cell collective migration. We find that Rap1 maintains cell contacts within the cluster, at least in part by promoting the organized distribution of E-cadherin at specific cell–cell junctions. Rap1 also restricts migratory protrusions to the front of the border cell cluster and promotes the extension of protrusions with normal dynamics. Further, Rap1 is required in the outer migratory border cells but not in the central nonmigratory polar cells. Such cell specificity correlates well with the spatial distribution of the inhibitory Rapgap1 protein, which is higher in polar cells than in border cells. We propose that precisely regulated Rap1 activity reinforces connections between cells and polarizes the cluster, thus facilitating the coordinated collective migration of border cells.

scholarly journals Src42A required for collective border cell migration in vivo

2017 ◽  
Author(s):  
Yasmin Sallak ◽  
Alba Yurani Torres ◽  
Hongyan Yin ◽  
Denise Montell
Keyword(s):  
Cell Migration ◽  
Cell Junctions ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Border Cell Migration ◽  
And Migration ◽  
Drosophila Ovary ◽  
E Cadherin

AbstractThe tyrosine kinase Src is over-expressed in numerous human cancers and is associated with poor prognosis. While Src has been extensively studied, its contributions to collective cell migration in vivo remain incompletely understood. Here we show that Src42A, but not Src64, is required for the specification and migration of the border cells in the Drosophila ovary, a well-developed and genetically tractable in vivo cell migration model. We found active Src42A enriched at border cell/nurse cell interfaces, where E-cadherin is less abundant, and depleted from border cell/border cell and border cell/polar cell junctions where E-cadherin is more stable, whereas total Src42A protein co-localizes with E-cadherin. Over-expression of wild type Src42A mislocalized Src activity and prevented border cell migration. Constitutively active or kinase dead forms of Src42A also impeded border cells. These findings establish border cells as a model for investigating the mechanisms of action of Src in cooperative, collective, cell-on-cell migration in vivo.

scholarly journals Coordination of protrusion dynamics within and between collectively migrating border cells by myosin II

2019 ◽  
Vol 30 (19) ◽  
pp. 2490-2502 ◽  
Author(s):  
Abhinava K. Mishra ◽  
James A. Mondo ◽  
Joseph P. Campanale ◽  
Denise J. Montell
Keyword(s):  
Myosin Ii ◽  
Resonance Energy ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Directional Information ◽  
Border Cell ◽  
Tumor Dissemination ◽  
Migrating Cells

Collective cell migration is emerging as a major driver of embryonic development, organogenesis, tissue homeostasis, and tumor dissemination. In contrast to individually migrating cells, collectively migrating cells maintain cell–cell adhesions and coordinate direction-sensing as they move. While nonmuscle myosin II has been studied extensively in the context of cells migrating individually in vitro, its roles in cells migrating collectively in three-dimensional, native environments are not fully understood. Here we use genetics, Airyscan microscopy, live imaging, optogenetics, and Förster resonance energy transfer to probe the localization, dynamics, and functions of myosin II in migrating border cells of the Drosophila ovary. We find that myosin accumulates transiently at the base of protrusions, where it functions to retract them. E-cadherin and myosin colocalize at border cell-border cell contacts and cooperate to transmit directional information. A phosphomimetic form of myosin is sufficient to convert border cells to a round morphology and blebbing migration mode. Together these studies demonstrate that distinct and dynamic pools of myosin II regulate protrusion dynamics within and between collectively migrating cells and suggest a new model for the role of protrusions in collective direction sensing in vivo.

scholarly journals Protein phosphatase 1 activity controls a balance between collective and single cell modes of migration

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yujun Chen ◽  
Nirupama Kotian ◽  
George Aranjuez ◽  
Lin Chen ◽  
C Luke Messer ◽  
...  
Keyword(s):  
Cell Migration ◽  
Single Cell ◽  
Protein Phosphatase ◽  
Single Cells ◽  
Cell Junctions ◽  
Protein Phosphatase 1 ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
And Migration

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.

scholarly journals PTEN inhibits AMPK to control collective migration

2021 ◽  
Author(s):  
Florent PEGLION ◽  
Lavinia Capuana ◽  
Isabelle Perfettini ◽  
Ben braithwaite ◽  
Flora Llense ◽  
...  
Keyword(s):  
Suppressor Gene ◽  
Cell Junctions ◽  
Migration And Invasion ◽  
Collective Cell Migration ◽  
Collective Migration ◽  
Vasp Phosphorylation ◽  
Ampk Activity ◽  
Cell Cell

PTEN is one of the most frequently mutated tumor suppressor gene in cancer. PTEN is generally altered in invasive cancers such as glioblastomas, but its function in collective cell migration and invasion is not fully characterized. Herein, we report that the loss of PTEN increases cell speed during collective migration of non-tumourous cells both in vitro and in vivo. We further show that loss of PTEN promotes LKB1-dependent phosphorylation and activation of the major metabolic regulator AMPK. In turn AMPK increases VASP phosphorylation, reduces VASP localization at cell-cell junctions and decreases the interjunctional transverse actin arcs at the leading front, provoking a weakening of cell-cell contacts and increasing migration speed. Targeting AMPK activity not only slows down PTEN-depleted cells, it also limits PTEN-null glioblastoma cell invasion, opening new opportunities to treat glioblastoma lethal invasiveness.

scholarly journals Nuclear lamins promote protrusion dynamics and collective, confined migration in vivo

2021 ◽  
Author(s):  
Lauren Penfield ◽  
Denise Montell
Keyword(s):  
Cell Migration ◽  
Nurse Cells ◽  
Border Cells ◽  
Collective Migration ◽  
Cell Nuclei ◽  
Migration Path ◽  
Border Cell ◽  
Nuclear Lamins ◽  
Border Cell Migration

Cells migrate collectively through confined environments during development and cancer metastasis. While the nucleus, a large and stiff organelle, impedes cell migration between non-deformable pillars in vitro, its function in vivo may vary depending on the microenvironment. Further, it is unknown how nuclei contribute to collective migration in vivo and whether nuclei in different positions within cell collectives experience different forces. Here, we use border cell migration in the fly ovary as an in vivo model to investigate the effects of confined, collective migration on nuclei and the contribution of nuclear lamins to migration. We found severe yet transient nuclear deformations occur, particularly in the leading cell, as border cells squeeze through tiny crevices between germline cells, termed nurse cells. Leading cells extend protrusions between nurse cells, which may pry open space to allow the cluster to advance. Here we report that the leading cell nuclei deformed as they moved into leading protrusions. Then as protrusions widened, the nucleus recovered a more circular shape. These data suggest that lead cell nuclei may help protrusions expand and thereby enlarge the migration path. To test how nuclei might promote or impede border cell migration, we investigated nuclear lamins, proteins that assemble into intermediate filaments and structurally support the nuclear envelope. Depletion of the Drosophila B-type lamin, Lam, from the outer, motile border cells, but not the inner, nonmotile polar cells, impeded border cell migration, whereas perturbations of the A-type lamin, LamC, did not. While wild type border cell clusters typically have one large leading protrusion as they delaminate from the anterior follicular epithelium, clusters depleted of B-type lamin had multiple, short-lived protrusions, resulting in unproductive cluster movement and failure to progress along the migration path. Further, border cell nuclei depleted of B-type lamins were small, formed blebs, and ruptured. Together, these data indicate that B-type lamin is requied for nuclear integrity, which in turn stabilizes the leading protrusion and promotes overall cluster polarization and collective movement through confined spaces.

scholarly journals Protein Phosphatase 1 activity controls a balance between collective and single cell modes of migration

2019 ◽  
Author(s):  
Yujun Chen ◽  
Nirupama Kotian ◽  
George Aranjuez ◽  
Lin Chen ◽  
C. Luke Messer ◽  
...  
Keyword(s):  
Cell Migration ◽  
Single Cell ◽  
Protein Phosphatase ◽  
Single Cells ◽  
Cell Junctions ◽  
Protein Phosphatase 1 ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Cell Cell

AbstractCollective 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 internal cell-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.

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

2019 ◽  
Author(s):  
Maureen C. Lamb ◽  
Kelsey K. Anliker ◽  
Tina L. Tootle
Keyword(s):  
Cell Migration ◽  
Cancer Metastasis ◽  
Collective Cell Migration ◽  
Nurse Cells ◽  
Border Cells ◽  
Border Cell ◽  
Migration Data ◽  
Border Cell Migration

AbstractFascin is an actin bundling protein that is essential for developmental cell migrations and promotes cancer metastasis. In addition to bundling actin, Fascin has several actin-independent roles. Border cell migration during Drosophila oogenesis provides an excellent model to study Fascin’s various roles during invasive, collective cell migration. Border cell migration requires Fascin. Fascin functions not only within the migrating border cells, but also within the nurse cells, the substrate for this migration. Loss of Fascin results in increased, shorter and mislocalized protrusions during migration. Data supports the model that Fascin promotes the activity of Enabled, an actin elongating factor, to regulate migration. Additionally, loss of Fascin inhibits border cell delamination. These defects are partially due to altered E-cadherin localization in the border cells; this is predicted to be an actin-independent role of Fascin. Overall, Fascin is essential for multiple aspects of this invasive, collective cell migration, and functions in both actin-dependent and -independent manners. These findings have implications beyond Drosophila, as border cell migration has emerged as a model to study mechanisms mediating cancer metastasis.

scholarly journals Distinct roles of tumor associated mutations in collective cell migration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rachel M. Lee ◽  
Michele I. Vitolo ◽  
Wolfgang Losert ◽  
Stuart S. Martin
Keyword(s):  
Collective Behavior ◽  
Metastatic Potential ◽  
Breast Epithelial Cell ◽  
Collective Cell Migration ◽  
Label Free ◽  
Collective Migration ◽  
Contrast Imaging ◽  
Pten Deletion

AbstractRecent evidence suggests that groups of cells are more likely to form clinically dangerous metastatic tumors, emphasizing the importance of understanding mechanisms underlying collective behavior. The emergent collective behavior of migrating cell sheets in vitro has been shown to be disrupted in tumorigenic cells but the connection between this behavior and in vivo tumorigenicity remains unclear. We use particle image velocimetry to measure a multidimensional migration phenotype for genetically defined human breast epithelial cell lines that range in their in vivo behavior from non-tumorigenic to aggressively metastatic. By using cells with controlled mutations, we show that PTEN deletion enhances collective migration, while Ras activation suppresses it, even when combined with PTEN deletion. These opposing effects on collective migration of two mutations that are frequently found in patient tumors could be exploited in the development of novel treatments for metastatic disease. Our methods are based on label-free phase contrast imaging, and thus could easily be applied to patient tumor cells. The short time scales of our approach do not require potentially selective growth, and thus in combination with label-free imaging would allow multidimensional collective migration phenotypes to be utilized in clinical assessments of metastatic potential.

scholarly journals Regulatory mechanisms required for DE-cadherin function in cell migration and other types of adhesion

2005 ◽  
Vol 170 (5) ◽  
pp. 803-812 ◽  
Author(s):  
Anne Pacquelet ◽  
Pernille Rørth
Keyword(s):  
Cell Migration ◽  
Cell Sorting ◽  
Model System ◽  
Regulatory Mechanisms ◽  
Border Cells ◽  
Specific Function ◽  
Additional Function ◽  
Border Cell ◽  
Cell Positioning

Cadherin-mediated adhesion can be regulated at many levels, as demonstrated by detailed analysis in cell lines. We have investigated the requirements for Drosophila melanogaster epithelial (DE) cadherin regulation in vivo. Investigating D. melanogaster oogenesis as a model system allowed the dissection of DE-cadherin function in several types of adhesion: cell sorting, cell positioning, epithelial integrity, and the cadherin-dependent process of border cell migration. We generated multiple fusions between DE-cadherin and α-catenin as well as point-mutated β-catenin and analyzed their ability to support these types of adhesion. We found that (1) although linking DE-cadherin to α-catenin is essential, regulation of the link is not required in any of these types of adhesion; (2) β-catenin is required only to link DE-cadherin to α-catenin; and (3) the cytoplasmic domain of DE-cadherin has an additional specific function for the invasive migration of border cells, which is conserved to other cadherins. The nature of this additional function is discussed.

scholarly journals Collective cell migration in development

2016 ◽  
Vol 212 (2) ◽  
pp. 143-155 ◽  
Author(s):  
Elena Scarpa ◽  
Roberto Mayor
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Collective Cell Migration ◽  
Germ Layer ◽  
Collective Migration ◽  
Developmental Models ◽  
Border Cell ◽  
Guidance Cues ◽  
Tracheal Branching

During embryonic development, tissues undergo major rearrangements that lead to germ layer positioning, patterning, and organ morphogenesis. Often these morphogenetic movements are accomplished by the coordinated and cooperative migration of the constituent cells, referred to as collective cell migration. The molecular and biomechanical mechanisms underlying collective migration of developing tissues have been investigated in a variety of models, including border cell migration, tracheal branching, blood vessel sprouting, and the migration of the lateral line primordium, neural crest cells, or head mesendoderm. Here we review recent advances in understanding collective migration in these developmental models, focusing on the interaction between cells and guidance cues presented by the microenvironment and on the role of cell–cell adhesion in mechanical and behavioral coupling of cells within the collective.

Sign in / Sign up

Export Citation Format

Share Document