Tissue self-organization based on collective cell migration by contact activation of locomotion and chemotaxis

Despite their central role in multicellular organization, navigation rules that dictate cell rearrangement remain largely undefined. Contact between neighboring cells and diffusive attractant molecules are two of the major determinants of tissue-level patterning; however, in most cases, molecular and developmental complexity hinders one from decoding the exact governing rules of individual cell movement. A primordial example of tissue patterning by cell rearrangement is found in the social amoebaDictyostelium discoideumwhere the organizing center or the “tip” self-organizes as a result of sorting of differentiating prestalk and prespore cells. By employing microfluidics and microsphere-based manipulation of navigational cues at the single-cell level, here we uncovered a previously overlooked mode ofDictyosteliumcell migration that is strictly directed by cell–cell contact. The cell–cell contact signal is mediated by E-set Ig-like domain-containing heterophilic adhesion molecules TgrB1/TgrC1 that act in trans to induce plasma membrane recruitment of the SCAR complex and formation of dendritic actin networks, and the resulting cell protrusion competes with those induced by chemoattractant cAMP. Furthermore, we demonstrate that both prestalk and prespore cells can protrude toward the contact signal as well as to chemotax toward cAMP; however, when given both signals, prestalk cells orient toward the chemoattractant, whereas prespore cells choose the contact signal. These data suggest a model of cell sorting by competing juxtacrine and diffusive cues, each with potential to drive its own mode of collective cell migration.

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Tissue self-organization based on collective cell migration by contact activation of locomotion and chemotaxis

10.1101/411306 ◽

2018 ◽

Author(s):

Taihei Fujimori ◽

Akihiko Nakajima ◽

Nao Shimada ◽

Satoshi Sawai

Keyword(s):

Cell Migration ◽

Individual Cell ◽

Cell Movement ◽

Tissue Level ◽

Cell Contact ◽

Collective Cell Migration ◽

Contact Activation ◽

Cell Rearrangement ◽

Cell Protrusion ◽

Cell Cell

AbstractDespite their central role in multicellular organization, navigation rules that dictate cell rearrangement remain much to be elucidated. Contact between neighboring cells and diffusive attractant molecules are two of the major determinants of tissue-level patterning, however in most cases, molecular and developmental complexity hinders one from decoding the exact governing rules of individual cell movement. A primordial example of tissue patterning by cell rearrangement is found in the social amoeba Dictyostelium discoideum where the organizing center or the ‘tip’ self-organize as a result of sorting of differentiating prestalk and prespore cells. Due to its relatively simple and conditional multicellularity, the system provides a rare case where the process can be fully dissected into individual cell behavior. By employing microfluidics and microsphere-based manipulation of navigational cues at the single-cell level, here we uncovered a previously overlooked mode of Dictyostelium cell migration that is strictly directed by cell-cell contact. The cell-cell contact signal is mediated by E-set Ig-like domain containing heterophilic adhesion molecules TgrB1/TgrC1 that act in trans to induce plasma membrane recruitment of SCAR complex and formation of dendritic actin networks, and the resulting cell protrusion competes with those induced by chemoattractant cAMP. Furthermore, we demonstrate that both prestalk and prespore cells can protrude towards the contact signal as well as to chemotax towards cAMP, however when given both signals, prestalk cells orient towards the chemoattractant whereas prespore cells choose the contact signal. These data suggest a new model of cell sorting by competing juxtacrine and diffusive cues each with potential to drive its own mode of collective cell migration. The present findings not only resolve the long standing question of how cells sort in Dictyostelium but also cast light on the remarkable parallels in collective cell migration that evolved independently in metazoa and amoebozoa.

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Hierarchical modeling of mechano-chemical dynamics of epithelial sheets across cells and tissue

Scientific Reports ◽

10.1038/s41598-021-83396-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yoshifumi Asakura ◽

Yohei Kondo ◽

Kazuhiro Aoki ◽

Honda Naoki

Keyword(s):

Wound Healing ◽

Cell Migration ◽

Continuum Model ◽

Tissue Level ◽

Chemical Signals ◽

Cellular Level ◽

Mathematical Framework ◽

Collective Cell Migration ◽

The Continuum ◽

Cell Cell

AbstractCollective cell migration is a fundamental process in embryonic development and tissue homeostasis. This is a macroscopic population-level phenomenon that emerges across hierarchy from microscopic cell-cell interactions; however, the underlying mechanism remains unclear. Here, we addressed this issue by focusing on epithelial collective cell migration, driven by the mechanical force regulated by chemical signals of traveling ERK activation waves, observed in wound healing. We propose a hierarchical mathematical framework for understanding how cells are orchestrated through mechanochemical cell-cell interaction. In this framework, we mathematically transformed a particle-based model at the cellular level into a continuum model at the tissue level. The continuum model described relationships between cell migration and mechanochemical variables, namely, ERK activity gradients, cell density, and velocity field, which could be compared with live-cell imaging data. Through numerical simulations, the continuum model recapitulated the ERK wave-induced collective cell migration in wound healing. We also numerically confirmed a consistency between these two models. Thus, our hierarchical approach offers a new theoretical platform to reveal a causality between macroscopic tissue-level and microscopic cellular-level phenomena. Furthermore, our model is also capable of deriving a theoretical insight on both of mechanical and chemical signals, in the causality of tissue and cellular dynamics.

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Non-junctional role of Cadherin3 in cell migration and contact inhibition of locomotion via domain-dependent, opposing regulation of Rac1

Scientific Reports ◽

10.1038/s41598-020-73862-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Takehiko Ichikawa ◽

Carsten Stuckenholz ◽

Lance A. Davidson

Keyword(s):

Cell Migration ◽

Contact Inhibition ◽

Cell Contact ◽

Collective Cell Migration ◽

Rac1 Activity ◽

Classical Cadherins ◽

Migration Assays ◽

Spatio Temporal ◽

Cell Cell

Abstract Classical cadherins are well-known adhesion molecules responsible for physically connecting neighboring cells and signaling this cell–cell contact. Recent studies have suggested novel signaling roles for “non-junctional” cadherins (NJCads); however, the function of cadherin signaling independent of cell–cell contacts remains unknown. In this study, mesendodermal cells and tissues from gastrula stage Xenopus laevis embryos demonstrate that deletion of extracellular domains of Cadherin3 (Cdh3; formerly C-cadherin in Xenopus) disrupts contact inhibition of locomotion. In both bulk Rac1 activity assays and spatio-temporal FRET image analysis, the extracellular and cytoplasmic Cdh3 domains disrupt NJCad signaling and regulate Rac1 activity in opposing directions. Stabilization of the cytoskeleton counteracted this regulation in single cell migration assays. Our study provides novel insights into adhesion-independent signaling by Cadherin3 and its role in regulating single and collective cell migration.

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Non-junctional Cadherin3 regulates cell migration and contact inhibition of locomotion via domain-dependent opposing regulations of Rac1

10.1101/750752 ◽

2019 ◽

Author(s):

Takehiko Ichikawa ◽

Carsten Stuckenholz ◽

Lance A. Davidson

Keyword(s):

Cell Migration ◽

Contact Inhibition ◽

Cell Contact ◽

Collective Cell Migration ◽

Cell Contacts ◽

Rac1 Activity ◽

Classical Cadherins ◽

The Stability ◽

Cell Cell

AbstractClassical cadherins are well-known primary adhesion molecules responsible for physically connecting neighboring cells and signaling the cell-cell contact. Recent studies have suggested novel signaling roles for “non-junctional” cadherins (Niessen and Gottardi, 2008; Padmanabhan et al., 2017); however, the function of cadherin signaling independent of cell-cell contacts remains unknown. In this study, we used mesendoderm cells and tissues from gastrula stage Xenopus laevis embryos to demonstrate that extracellular and cytoplasmic cadherin domains regulate Rac1 in opposing directions in the absence of cell-cell contacts. Furthermore, we found that non-junctional cadherins regulate contact inhibition of locomotion (CIL) during gastrulation through alterations in the stability of the cytoskeleton. Live FRET imaging of Rac1 activity illustrated how non-junction cadherin3 (formerly C-cadherin) spatio-temporally regulates CIL. Our study provides novel insights into adhesion-independent signaling by cadherin3 and its role in regulating single and collective cell migration in vivo.

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M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell–cell adhesion during collective cell migration

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1805919116 ◽

2019 ◽

Vol 116 (9) ◽

pp. 3536-3545 ◽

Cited By ~ 8

Author(s):

Pradeep Kota ◽

Elizabeth M. Terrell ◽

Daniel A. Ritt ◽

Christine Insinna ◽

Christopher J. Westlake ◽

...

Keyword(s):

Cell Migration ◽

Dynamic Control ◽

Cell Movement ◽

Cell Junction ◽

Collective Cell Migration ◽

Dynamic Regulation ◽

P120 Catenin ◽

Mcf10a Cells ◽

E Cadherin ◽

Cell Cell

Collective cell migration is required for normal embryonic development and contributes to various biological processes, including wound healing and cancer cell invasion. The M-Ras GTPase and its effector, the Shoc2 scaffold, are proteins mutated in the developmental RASopathy Noonan syndrome, and, here, we report that activated M-Ras recruits Shoc2 to cell surface junctions where M-Ras/Shoc2 signaling contributes to the dynamic regulation of cell–cell junction turnover required for collective cell migration. MCF10A cells expressing the dominant-inhibitory M-RasS27N variant or those lacking Shoc2 exhibited reduced junction turnover and were unable to migrate effectively as a group. Through further depletion/reconstitution studies, we found that M-Ras/Shoc2 signaling contributes to junction turnover by modulating the E-cadherin/p120-catenin interaction and, in turn, the junctional expression of E-cadherin. The regulatory effect of the M-Ras/Shoc2 complex was mediated at least in part through the phosphoregulation of p120-catenin and required downstream ERK cascade activation. Strikingly, cells rescued with the Noonan-associated, myristoylated-Shoc2 mutant (Myr-Shoc2) displayed a gain-of-function (GOF) phenotype, with the cells exhibiting increased junction turnover and reduced E-cadherin/p120-catenin binding and migrating as a faster but less cohesive group. Consistent with these results, Noonan-associated C-Raf mutants that bypass the need for M-Ras/Shoc2 signaling exhibited a similar GOF phenotype when expressed in Shoc2-depleted MCF10A cells. Finally, expression of the Noonan-associated Myr-Shoc2 or C-Raf mutants, but not their WT counterparts, induced gastrulation defects indicative of aberrant cell migration in zebrafish embryos, further demonstrating the function of the M-Ras/Shoc2/ERK cascade signaling axis in the dynamic control of coordinated cell movement.

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