scholarly journals Fascin limits Myosin activity within Drosophila border cells to control substrate stiffness and promote migration

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Maureen C Lamb ◽  
Chathuri P Kaluarachchi ◽  
Thiranjeewa I Lansakara ◽  
Samuel Q Mellentine ◽  
Yiling Lan ◽  
...  
Keyword(s):  
Cell Migration ◽  
Nurse Cell ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Substrate Stiffness ◽  
Cell Stiffness ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Border Cell Migration

A key regulator of collective cell migrations, which drive development and cancer metastasis, is substrate stiffness. Increased substrate stiffness promotes migration and is controlled by Myosin. Using Drosophila border cell migration as a model of collective cell migration, we identify, for the first time, that the actin bundling protein Fascin limits Myosin activity in vivo. Loss of Fascin results in: increased activated Myosin on the border cells and their substrate, the nurse cells; decreased border cell Myosin dynamics; and increased nurse cell stiffness as measured by atomic force microscopy. Reducing Myosin restores on-time border cell migration in fascin mutant follicles. Further, Fascin’s actin bundling activity is required to limit Myosin activation. Surprisingly, we find that Fascin regulates Myosin activity in the border cells to control nurse cell stiffness to promote migration. Thus, these data shift the paradigm from a substrate stiffness-centric model of regulating migration, to uncover that collectively migrating cells play a critical role in controlling the mechanical properties of their substrate in order to promote their own migration. This understudied means of mechanical regulation of migration is likely conserved across contexts and organisms, as Fascin and Myosin are common regulators of cell migration.

scholarly journals Fascin limits Myosin activity within Drosophila border cells to control substrate stiffness and promote migration

2021 ◽  
Author(s):  
Maureen C. Lamb ◽  
Chathuri P. Kaluarachchi ◽  
Thiranjeewa I. Lansakara ◽  
Yiling Lan ◽  
Alexei V. Tivanski ◽  
...  
Keyword(s):  
Cell Migration ◽  
Nurse Cell ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Substrate Stiffness ◽  
Cell Stiffness ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Border Cell Migration

AbstractA key regulator of collective cell migrations, which drive development and cancer metastasis, is substrate stiffness. Increased substrate stiffness promotes migration and is controlled by Myosin. Using Drosophila border cell migration as a model of collective cell migration, we identify, for the first time, that the actin bundling protein Fascin limits Myosin activity in vivo. Loss of Fascin results in: increased activated Myosin on the border cells and their substrate, the nurse cells; decreased border cell Myosin dynamics; and increased nurse cell stiffness as measured by atomic force microscopy. Reducing Myosin restores on-time border cell migration in fascin mutant follicles. Further, Fascin’s actin bundling activity is required to limit Myosin activation. Surprisingly, we find that Fascin regulates Myosin activity in the border cells to control nurse cell stiffness to promote migration. Thus, these data shift the paradigm from a substrate stiffness-centric model of regulating migration, to uncover that collectively migrating cells play a critical role in controlling the mechanical properties of their substrate in order to promote their own migration. This new means of mechanical regulation of migration is likely conserved across contexts and organisms, as Fascin and Myosin are common regulators of 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 Tousled-like kinase regulates cytokine-mediated communication between cooperating cell types during collective border cell migration

2016 ◽  
Vol 27 (1) ◽  
pp. 12-19 ◽  
Author(s):  
Wenjuan Xiang ◽  
Dabing Zhang ◽  
Denise J. Montell
Keyword(s):  
Cell Migration ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Cell Types ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Stat Signaling ◽  
Border Cell Migration

Collective cell migration is emerging as a major contributor to normal development and disease. Collective movement of border cells in the Drosophila ovary requires cooperation between two distinct cell types: four to six migratory cells surrounding two immotile cells called polar cells. Polar cells secrete a cytokine, Unpaired (Upd), which activates JAK/STAT signaling in neighboring cells, stimulating their motility. Without Upd, migration fails, causing sterility. Ectopic Upd expression is sufficient to stimulate motility in otherwise immobile cells. Thus regulation of Upd is key. Here we report a limited RNAi screen for nuclear proteins required for border cell migration, which revealed that the gene encoding Tousled-like kinase (Tlk) is required in polar cells for Upd expression without affecting polar cell fate. In the absence of Tlk, fewer border cells are recruited and motility is impaired, similar to inhibition of JAK/STAT signaling. We further show that Tlk in polar cells is required for JAK/STAT activation in border cells. Genetic interactions further confirmed Tlk as a new regulator of Upd/JAK/STAT signaling. These findings shed light on the molecular mechanisms regulating the cooperation of motile and nonmotile cells during collective invasion, a phenomenon that may also drive metastatic cancer.

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 Microtubule deacetylation reduces cell stiffness to allow the onset of collective cell migration in vivo

2021 ◽  
Author(s):  
Cristian L Marchant ◽  
Abdul N Malmi-Kakkada ◽  
Jaime A Espina ◽  
Elias H Barriga
Keyword(s):  
Cell Migration ◽  
Cancer Metastasis ◽  
Mechanical Response ◽  
Substrate Stiffness ◽  
Cell Stiffness ◽  
Collective Cell Migration ◽  
Force Microscopy ◽  
Atomic Force

Embryogenesis, tissue repair and cancer metastasis rely on collective cell migration (CCM). In vitro studies propose that migrating cells are stiffer when exposed to stiff substrates, known to allow CCM, but softer when plated in compliant non-permissive surfaces. Here, by combining in vivo atomic force microscopy (iAFM) and modelling we reveal that to collectively migrate in vivo, cells require to dynamically decrease their stiffness in response to the temporal stiffening of their native substrate. Moreover, molecular and mechanical perturbations of embryonic tissues uncover that this unexpected cell mechanical response is achieved by a new mechanosensitive pathway involving Piezo1-mediated microtubule deacetylation. Finally, lowering microtubule acetylation and consequently cell stiffness was sufficient to allow CCM in soft non-permissive substrates, suggesting that a fixed value of substrate stiffness is not as essential for CCM as it is reaching an optimal cell-to-substrate stiffness value. These in vivo insights on cell-to-substrate mechanical interplay have major implications to our re-interpretation of physiological and pathological contexts.

Two distinct roles for Ras in a developmentally regulated cell migration

Development ◽  
1996 ◽  
Vol 122 (2) ◽  
pp. 409-418 ◽  
Author(s):  
T. Lee ◽  
L. Feig ◽  
D.J. Montell
Keyword(s):  
Cell Migration ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Critical Role ◽  
Dominant Negative ◽  
Follicle Cells ◽  
Border Cells ◽  
Ras Protein ◽  
Border Cell ◽  
Border Cell Migration

Receptor tyrosine kinases have been shown to promote cell movement in a variety of systems. The Ras protein, a well-documented downstream effector for receptor tyrosine kinases, may contribute to receptor tyrosine kinase-mediated motility. In the present study, we have examined the role of Ras in the migration of a small subset of follicle cells, known as the border cells, during Drosophila oogenesis. A dominant-negative Ras protein inhibited cell migration when expressed specifically in border cells during the period when these cells normally migrate. When expressed prior to migration, dominant-negative Ras promoted premature initiation of migration. Conversely, expression of constitutively active Ras prior to migration resulted in a significant delay in the initiation step. Furthermore, the defect in initiation of border cell migration found in slbo1, a mutation at the locus that encodes Drosophila C/EBP, was largely rescued by reducing Ras activity in border cells prior to migration. Taken together, these observations indicate that Ras activity plays two distinct roles in the border cells: (1) reduction in Ras activity promotes the initiation of that migration process and (2) Ras activity is required during border cell migration. We further examined the possible involvement of two downstream effectors of Ras in border cell migration. Raf activity was dispensable to border cell migration while reduced Ral activity inhibited initiation. We therefore suggest that Ras plays a critical role in the dynamic regulation of border cell migration via a Raf-independent pathway.

scholarly journals Collective border cell migration requires the zinc transporter Catsup to limit endoplasmic reticulum stress

2021 ◽  
Author(s):  
XIAORAN GUO ◽  
Wei Dai ◽  
Denise Montell
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Migration ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Transmembrane Protein ◽  
Zinc Transporter ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Border Cell Migration

Collective cell migration is critical for normal development, wound healing, and in tumor progression and metastasis. Border cells in the Drosophila ovary provide a genetically tractable model to identify molecular mechanisms that drive this important cell behavior. In an unbiased screen for defects in border cell migration in mosaic clones, we identified a mutation in the catsup gene. Catsup, the Drosophila ortholog of Zip7, is a large, multifunctional, transmembrane protein of the endoplasmic reticulum (ER), which has been reported to negatively regulate catecholamine biosynthesis, to regulate Notch signaling, to function as a zinc transporter, and to limit ER stress. Here we report that catsup knockdown caused ER stress in border cells and that ectopic induction of ER stress was sufficient to block migration. Notch and EGFR trafficking were also disrupted. Wild type Catsup rescued the migration defect but point mutations known to disrupt the zinc ion transport of Zip7 did not. We conclude that migrating cells are particularly susceptible to defects in zinc transport and ER homeostasis.

The breathless FGF receptor homolog, a downstream target of Drosophila C/EBP in the developmental control of cell migration

Development ◽  
1995 ◽  
Vol 121 (8) ◽  
pp. 2255-2263 ◽  
Author(s):  
A.M. Murphy ◽  
T. Lee ◽  
C.M. Andrews ◽  
B.Z. Shilo ◽  
D.J. Montell
Keyword(s):  
Cell Migration ◽  
Molecular Mechanisms ◽  
Follicle Cells ◽  
Border Cells ◽  
Timely Initiation ◽  
Fgf Receptor ◽  
Border Cell ◽  
Downstream Target ◽  
Border Cell Migration ◽  
Factor C

To investigate the molecular mechanisms responsible for the temporal and spatial control of cell movements during development, we have been studying the migration of a small group of follicle cells, called the border cells, in the Drosophila ovary. Timely initiation of border cell migration requires the product of the slow border cells (slbo) locus, which encodes the Drosophila homolog of the transcription factor C/EBP. Here we report evidence that one target of C/EBP in the control of border cell migration is the FGF receptor homolog encoded by the breathless (btl) locus. btl expression in the ovary was border cell-specific, beginning just prior to the migration, and this expression was reduced in slbo mutants. btl mutations dominantly enhanced the border cell migration defects found in weak slbo alleles. Furthermore, C/EBP-independent btl expression was able to rescue the migration defects of hypomorphic slbo alleles. Purified Drosophila C/EBP bound eight sites in the btl 5′ flanking region by DNAse I footprinting. Taken together these results suggest that btl is a key, direct target for C/EBP in the regulation of border cell migration.

Jing: a downstream target of slbo required for developmental control of border cell migration

Development ◽  
2001 ◽  
Vol 128 (3) ◽  
pp. 321-330 ◽  
Author(s):  
Y. Liu ◽  
D.J. Montell
Keyword(s):  
Cell Migration ◽  
Leucine Zipper ◽  
Inducible Promoter ◽  
Regulatory Sequence ◽  
Border Cells ◽  
Border Cell ◽  
Downstream Target ◽  
Border Cell Migration ◽  
Factor C ◽  
Drosophila Ovary

Epithelial to mesenchymal transitions and cell migration are important features of embryonic development and tumor metastasis. We are employing a systematic genetic approach to study the border cells in the Drosophila ovary, as a simple model for these cellular behaviors. Previously we found that expression of the basic-region/leucine zipper transcription factor, C/EBP, is required for the border cells to initiate their migration. Here we report the identification of a second nuclear factor, named JING (which means ‘still’), that is required for initiation of border cell migration. The jing locus was identified in a screen for mutations that cause border cell migration defects in mosaic clones. The jing mutant phenotype resembles that of slbo mutations, which disrupt the Drosophila C/EBP gene, but is distinct from other classes of border cell migration mutants. Expression of a jing-lacZ reporter in border cells requires C/EBP. Moreover, expression of jing from a heat-inducible promoter rescues the border cell migration defects of hypomorphic slbo mutants. The JING protein is most closely related to a mouse protein, AEBP2, which was identified on the basis of its ability to bind a small regulatory sequence within the adipocyte AP2 gene to which mammalian C/EBP also binds. We propose that the need to coordinate cell differentiation with nutritional status may be the link between mammalian adipocytes and Drosophila border cells that led to the conservation of C/EBP and AEBP2.

scholarly journals Mechanochemical coupling and junctional forces during collective cell migration

2019 ◽  
Author(s):  
J. Bui ◽  
D. E. Conway ◽  
R. L. Heise ◽  
S.H. Weinberg
Keyword(s):  
Cell Migration ◽  
Rho Gtpases ◽  
Cancer Metastasis ◽  
Rho Gtpase ◽  
Critical Role ◽  
Leading Edge ◽  
Collective Cell Migration ◽  
Gtpase Activity ◽  
Modeling Framework ◽  
Cell Cell

ABSTRACTCell migration, a fundamental physiological process in which cells sense and move through their surrounding physical environment, plays a critical role in development and tissue formation, as well as pathological processes, such as cancer metastasis and wound healing. During cell migration, dynamics are governed by the bidirectional interplay between cell-generated mechanical forces and the activity of Rho GTPases, a family of small GTP-binding proteins that regulate actin cytoskeleton assembly and cellular contractility. These interactions are inherently more complex during the collective migration of mechanically coupled cells, due to the additional regulation of cell-cell junctional forces. In this study, we present a minimal modeling framework to simulate the interactions between mechanochemical signaling in individual cells and interactions with cell-cell junctional forces during collective cell migration. We find that migration of individual cells depends on the feedback between mechanical tension and Rho GTPase activity in a biphasic manner. During collective cell migration, waves of Rho GTPase activity mediate mechanical contraction/extension and thus synchronization throughout the tissue. Further, cell-cell junctional forces exhibit distinct spatial patterns during collective cell migration, with larger forces near the leading edge. Larger junctional force magnitudes are associated with faster collective cell migration and larger tissue size. Simulations of heterogeneous tissue migration exhibit a complex dependence on the properties of both leading and trailing cells. Computational predictions demonstrate that collective cell migration depends on both the emergent dynamics and interactions between cellular-level Rho GTPase activity and contractility, and multicellular-level junctional forces.

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