scholarly journals Stretch-induced endogenous electric fields drive neural crest directed collective cell migration in vivo

2021 ◽  
Author(s):  
Fernando Ferreira ◽  
Sofia Moreira ◽  
Elias H Barriga
Keyword(s):  
Cell Migration ◽  
Neural Crest ◽  
Electric Fields ◽  
Embryonic Cell ◽  
Collective Cell Migration ◽  
Convergent Extension ◽  
Topological Features ◽  
Stretch Activated Channels

Directed collective cell migration (dCCM) is essential for morphogenesis. Cell clusters migrate in inherently complex in vivo environments composed of chemical, electrical, mechanical as well as topological features. While these environmental factors have been shown to allow dCCM in vitro, our understanding of dCCM in vivo is mostly limited to chemical guidance. Thus, despite its wide biological relevance, the mechanisms that guide dCCM in vivo remain unclear. To address this, we study endogenous electric fields in relation to the migratory environment of the Xenopus laevis cephalic neural crest, an embryonic cell population that collectively and directionally migrates in vivo. Combining bioelectrical, biomechanical and molecular tools, we show that endogenous electric fields drive neural crest dCCM via electrotaxis in vivo. Moreover, we identify the voltage-sensitive phosphatase 1 (Vsp1) as a key component of the molecular mechanism used by neural crest cells to transduce electric fields into a directional cue. Furthermore, Vsp1 function is specifically required for electrotaxis, being dispensable for cell motility and chemotaxis. Finally, we reveal that endogenous electric fields are mechanoelectrically established. Mechanistically, convergent extension movements of the neural fold generate membrane tension, which in turn opens stretch-activated channels to mobilise the ions required to fuel electric fields. Overall, our results reveal a mechanism of cell guidance, where electrotaxis emerges from the mechanoelectrical and molecular interplay between neighbouring tissues. More broadly, our data contribute to validate the, otherwise understudied, functions of endogenous bioelectrical stimuli in morphogenetic processes.

scholarly journals How inhibitory cues can both constrain and promote cell migration

2016 ◽  
Vol 213 (5) ◽  
pp. 505-507 ◽  
Author(s):  
Marianne E. Bronner
Keyword(s):  
Mathematical Modeling ◽  
Cell Migration ◽  
Neural Crest ◽  
Neural Crest Cells ◽  
Collective Cell Migration ◽  
Promote Cell Migration ◽  
Neural Crest Migration ◽  
Physical Boundary

Collective cell migration is a common feature in both embryogenesis and metastasis. By coupling studies of neural crest migration in vivo and in vitro with mathematical modeling, Szabó et al. (2016, J. Cell Biol., http://dx.doi.org/10.1083/jcb.201602083) demonstrate that the proteoglycan versican forms a physical boundary that constrains neural crest cells to discrete streams, in turn facilitating their migration.

scholarly journals In vivo confinement promotes collective migration of neural crest cells

2016 ◽  
Vol 213 (5) ◽  
pp. 543-555 ◽  
Author(s):  
András Szabó ◽  
Manuela Melchionda ◽  
Giancarlo Nastasi ◽  
Mae L. Woods ◽  
Salvatore Campo ◽  
...  
Keyword(s):  
Cell Migration ◽  
Neural Crest ◽  
Neural Crest Cells ◽  
Optimal Number ◽  
Collective Cell Migration ◽  
Collective Migration ◽  
Extracellular Matrix Molecule ◽  
Experimental Approaches

Collective cell migration is fundamental throughout development and in many diseases. Spatial confinement using micropatterns has been shown to promote collective cell migration in vitro, but its effect in vivo remains unclear. Combining computational and experimental approaches, we show that the in vivo collective migration of neural crest cells (NCCs) depends on such confinement. We demonstrate that confinement may be imposed by the spatiotemporal distribution of a nonpermissive substrate provided by versican, an extracellular matrix molecule previously proposed to have contrasting roles: barrier or promoter of NCC migration. We resolve the controversy by demonstrating that versican works as an inhibitor of NCC migration and also acts as a guiding cue by forming exclusionary boundaries. Our model predicts an optimal number of cells in a given confinement width to allow for directional migration. This optimum coincides with the width of neural crest migratory streams analyzed across different species, proposing an explanation for the highly conserved nature of NCC streams during development.

scholarly journals Emergence of single cell mechanical behavior and polarity within epithelial monolayers drives collective cell migration

2019 ◽  
Author(s):  
Shreyansh Jain ◽  
Victoire M.L. Cachoux ◽  
Gautham H.N.S. Narayana ◽  
Simon de Beco ◽  
Joseph D’Alessandro ◽  
...  
Keyword(s):  
Cell Migration ◽  
Single Cell ◽  
Large Scale ◽  
Cancer Metastasis ◽  
Cell Junctions ◽  
Collective Cell Migration ◽  
Convergent Extension ◽  
Cell Dynamics

The directed migration of cell collectives is essential in various physiological processes, such as epiboly, intestinal epithelial turnover, and convergent extension during morphogenesis as well as during pathological events like wound healing and cancer metastasis1,2. Collective cell migration leads to the emergence of coordinated movements over multiple cells. Our current understanding emphasizes that these movements are mainly driven by large-scale transmission of signals through adherens junctions3,4. In this study, we show that collective movements of epithelial cells can be triggered by polarity signals at the single cell level through the establishment of coordinated lamellipodial protrusions. We designed a minimalistic model system to generate one-dimensional epithelial trains confined in ring shaped patterns that recapitulate rotational movements observed in vitro in cellular monolayers and in vivo in genitalia or follicular cell rotation5–7. Using our system, we demonstrated that cells follow coordinated rotational movements after the establishment of directed Rac1-dependent polarity over the entire monolayer. Our experimental and numerical approaches show that the maintenance of coordinated migration requires the acquisition of a front-back polarity within each single cell but does not require the maintenance of cell-cell junctions. Taken together, these unexpected findings demonstrate that collective cell dynamics in closed environments as observed in multiple in vitro and in vivo situations5,6,8,9 can arise from single cell behavior through a sustained memory of cell polarity.

scholarly journals Lamellipodin and the Scar/WAVE complex cooperate to promote cell migration in vivo

2013 ◽  
Vol 203 (4) ◽  
pp. 673-689 ◽  
Author(s):  
Ah-Lai Law ◽  
Anne Vehlow ◽  
Maria Kotini ◽  
Lauren Dodgson ◽  
Daniel Soong ◽  
...  
Keyword(s):  
Cell Migration ◽  
Neural Crest ◽  
Neural Crest Cell ◽  
Direct Interaction ◽  
Dependent Manner ◽  
Border Cell ◽  
Promote Cell Migration ◽  
Wave Complex

Cell migration is essential for development, but its deregulation causes metastasis. The Scar/WAVE complex is absolutely required for lamellipodia and is a key effector in cell migration, but its regulation in vivo is enigmatic. Lamellipodin (Lpd) controls lamellipodium formation through an unknown mechanism. Here, we report that Lpd directly binds active Rac, which regulates a direct interaction between Lpd and the Scar/WAVE complex via Abi. Consequently, Lpd controls lamellipodium size, cell migration speed, and persistence via Scar/WAVE in vitro. Moreover, Lpd knockout mice display defective pigmentation because fewer migrating neural crest-derived melanoblasts reach their target during development. Consistently, Lpd regulates mesenchymal neural crest cell migration cell autonomously in Xenopus laevis via the Scar/WAVE complex. Further, Lpd’s Drosophila melanogaster orthologue Pico binds Scar, and both regulate collective epithelial border cell migration. Pico also controls directed cell protrusions of border cell clusters in a Scar-dependent manner. Taken together, Lpd is an essential, evolutionary conserved regulator of the Scar/WAVE complex during cell migration in vivo.

scholarly journals Self-organized cell migration across scales – from single cell movement to tissue formation

Development ◽  
2021 ◽  
Vol 148 (7) ◽  
pp. dev191767
Author(s):  
Jessica Stock ◽  
Andrea Pauli
Keyword(s):  
Cell Migration ◽  
Multiple Scales ◽  
Single Cells ◽  
Cell Movement ◽  
Biological Response ◽  
Collective Cell Migration ◽  
Theoretical Concepts ◽  
Self Organizing

ABSTRACTSelf-organization is a key feature of many biological and developmental processes, including cell migration. Although cell migration has traditionally been viewed as a biological response to extrinsic signals, advances within the past two decades have highlighted the importance of intrinsic self-organizing properties to direct cell migration on multiple scales. In this Review, we will explore self-organizing mechanisms that lay the foundation for both single and collective cell migration. Based on in vitro and in vivo examples, we will discuss theoretical concepts that underlie the persistent migration of single cells in the absence of directional guidance cues, and the formation of an autonomous cell collective that drives coordinated migration. Finally, we highlight the general implications of self-organizing principles guiding cell migration for biological and medical research.

scholarly journals α4/α9 Integrins Coordinate Epithelial Cell Migration Through Local Suppression of MAP Kinase Signaling Pathways

2021 ◽  
Vol 9 ◽  
Author(s):  
Willow Hight-Warburton ◽  
Robert Felix ◽  
Andrew Burton ◽  
Hannah Maple ◽  
Magda S. Chegkazi ◽  
...  
Keyword(s):  
Cell Migration ◽  
Protein Complexes ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Collective Cell Migration ◽  
Keratinocyte Proliferation ◽  
Basal Keratinocytes ◽  
Keratinocyte Cell

Adhesion of basal keratinocytes to the underlying extracellular matrix (ECM) plays a key role in the control of skin homeostasis and response to injury. Integrin receptors indirectly link the ECM to the cell cytoskeleton through large protein complexes called focal adhesions (FA). FA also function as intracellular biochemical signaling platforms to enable cells to respond to changing extracellular cues. The α4β1 and α9β1 integrins are both expressed in basal keratinocytes, share some common ECM ligands, and have been shown to promote wound healing in vitro and in vivo. However, their roles in maintaining epidermal homeostasis and relative contributions to pathological processes in the skin remain unclear. We found that α4β1 and α9β1 occupied distinct regions in monolayers of a basal keratinocyte cell line (NEB-1). During collective cell migration (CCM), α4 and α9 integrins co-localized along the leading edge. Pharmacological inhibition of α4β1 and α9β1 integrins increased keratinocyte proliferation and induced a dramatic change in cytoskeletal remodeling and FA rearrangement, detrimentally affecting CCM. Further analysis revealed that α4β1/α9β1 integrins suppress extracellular signal-regulated kinase (ERK1/2) activity to control migration through the regulation of downstream kinases including Mitogen and Stress Activated Kinase 1 (MSK1). This work demonstrates the roles of α4β1 and α9β1 in regulating migration in response to damage cues.

scholarly journals DAN (NBL1) promotes collective neural crest migration by restraining uncontrolled invasion

2017 ◽  
Vol 216 (10) ◽  
pp. 3339-3354 ◽  
Author(s):  
Rebecca McLennan ◽  
Caleb M. Bailey ◽  
Linus J. Schumacher ◽  
Jessica M. Teddy ◽  
Jason A. Morrison ◽  
...  
Keyword(s):  
Cell Migration ◽  
Neural Crest ◽  
Metastatic Melanoma ◽  
Neural Crest Cell ◽  
Bmp Signaling ◽  
Loss Of Function ◽  
Neural Crest Cell Migration ◽  
Crest Cell

Neural crest cells are both highly migratory and significant to vertebrate organogenesis. However, the signals that regulate neural crest cell migration remain unclear. In this study, we test the function of differential screening-selected gene aberrant in neuroblastoma (DAN), a bone morphogenetic protein (BMP) antagonist we detected by analysis of the chick cranial mesoderm. Our analysis shows that, before neural crest cell exit from the hindbrain, DAN is expressed in the mesoderm, and then it becomes absent along cell migratory pathways. Cranial neural crest and metastatic melanoma cells avoid DAN protein stripes in vitro. Addition of DAN reduces the speed of migrating cells in vivo and in vitro, respectively. In vivo loss of function of DAN results in enhanced neural crest cell migration by increasing speed and directionality. Computer model simulations support the hypothesis that DAN restrains cell migration by regulating cell speed. Collectively, our results identify DAN as a novel factor that inhibits uncontrolled neural crest and metastatic melanoma invasion and promotes collective migration in a manner consistent with the inhibition of BMP signaling.

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.

scholarly journals The mechanosensitive channel Piezo1 cooperates with Semaphorin to control neural crest migration

Development ◽  
2021 ◽  
Author(s):  
Brenda Canales Coutiño ◽  
Roberto Mayor
Keyword(s):  
Cell Migration ◽  
Neural Crest ◽  
Embryonic Cell ◽  
Extracellular Signals ◽  
Rac1 Activity ◽  
Cytoskeletal Dynamics ◽  
Mechanosensitive Ion Channel ◽  
Neural Crest Migration

Cells are permanently exposed to a multitude of different kind of signals; however how cells respond to simultaneous extracellular signals within a complex in vivo environment is poorly understood. Here, we studied the role of the mechanosensitive ion channel Piezo1 on the migration of the neural crest (NC), a multipotent embryonic cell population. We identify that Piezo1 is required for the migration of Xenopus cephalic NC. We show that loss of Piezo1 promotes focal adhesion turnover and cytoskeletal dynamics by controlling Rac1 activity, leading to increased speed of migration. Moreover, overactivation of Rac1, due to Piezo1 inhibition, counteracts cell migration inhibitory signals by Semaphorins 3A and 3F, generating aberrant neural crest invasion in vivo. Thus, we find that, for directional migration in vivo, neural crest cells require a tight regulation of Rac1, by Semaphorins and Piezo1. We reveal here that a balance between a myriad of signals through Rac1 dictates cell migration in vivo, a mechanism that is likely to be conserved in other cell migration processes.

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