Migrations cellulaires collectives

International audienceL’étude de la migration cellulaire, d’abord focalisée sur les mécanismes régissant la motilité au niveau d’une cellule unique, incorpore désormais les phénomènes coopératifs à l’échelle d’un groupe de cellules. Ces migrations dites collectives se produisent dans des contextes physiologiques ou pathologiques. Dans cette synthèse, nous discuterons les points qui permettent de définir le caractère collectif d’une migration. Nous aborderons les principaux concepts régissant les migrations collectives de tissus épithéliaux et mésenchymateux, et, plus particulièrement, les mécanismes régulant la polarité et orientant la direction des cellules

In vivo topology converts competition for cell-matrix adhesion into directional migration

International audienceWhen migrating in vivo, cells are exposed to numerous conflicting signals: chemokines, repellents, extracellular matrix, growth factors. The roles of several of these molecules have been studied individually in vitro or in vivo, but we have yet to understand how cells integrate them. To start addressing this question, we used the cephalic neural crest as a model system and looked at the roles of its best examples of positive and negative signals: stromal-cell derived factor 1 (Sdf1/Cxcl12) and class3-Semaphorins. Here we show that Sdf1 and Sema3A antagonistically control cell-matrix adhesion via opposite effects on Rac1 activity at the single cell level. Directional migration at the population level emerges as a result of global Semaphorin-dependent confinement and broad activation of adhesion by Sdf1 in the context of a biased Fibronectin distribution. These results indicate that uneven in vivo topology renders the need for precise distribution of secreted signals mostly dispensable

Cadherin Switch during EMT in Neural Crest Cells Leads to Contact Inhibition of Locomotion via Repolarization of Forces

Contact inhibition of locomotion (CIL) is the process through which cells move away from each other after cell-cell contact, and it contributes to malignant invasion and developmental migration. Various cell types exhibit CIL, whereas others remain in contact after collision and may form stable junctions. To investigate what determines this differential behavior, we study neural crest cells, a migratory stem cell population whose invasiveness has been likened to cancer metastasis. By comparing pre-migratory and migratory neural crest cells, we show that the switch from E- to N-cadherin during EMT is essential for acquisition of CIL behavior. Loss of E-cadherin leads to repolarization of protrusions, via p120 and Rac1, resulting in a redistribution of forces from intercellular tension to cell-matrix adhesions, which break down the cadherin junction. These data provide insight into the balance of physical forces that contributes to CIL in cells in vivo.</p

Chase-and-run between adjacent cell populations promotes directional collective migration

Collective cell migration in morphogenesis and cancer progression often involves the coordination of multiple cell types. How reciprocal interactions between adjacent cell populations lead to new emergent behaviours remains unknown. Here we studied the interaction between neural crest (NC) cells, a highly migratory cell population, and placodal cells, an epithelial tissue that contributes to sensory organs. We found that NC cells chase placodal cells by chemotaxis, and placodal cells run when contacted by NC. Chemotaxis to Sdf1 underlies the chase, and repulsion involving PCP and N-cadherin signalling is responsible for the run. This chase-and-run requires the generation of asymmetric forces, which depend on local inhibition of focal adhesions. The cell interactions described here are essential for correct NC migration and for segregation of placodes in vivo and are likely to represent a general mechanism of coordinated migration

Leaders in collective migration: are front cells really endowed with a particular set of skills? [version 1; referees: 2 approved]

Collective cell migration is the coordinated movement emerging from the interaction of at least two cells. In multicellular organisms, collective cell migration is ubiquitous. During development, embryonic cells often travel in numbers, whereas in adults, epithelial cells close wounds collectively. There is often a division of labour and two categories of cells have been proposed: leaders and followers. These two terms imply that followers are subordinated to leaders whose proposed broad range of actions significantly biases the direction of the group of cells towards a specific target. These two terms are also tied to topology. Leaders are at the front while followers are located behind them. Here, we review recent work on some of the main experimental models for collective cell migration, concluding that leader-follower terminology may not be the most appropriate. It appears that not all collectively migrating groups are driven by cells located at the front. Moreover, the qualities that define leaders (pathfinding, traction forces and matrix remodelling) are not specific to front cells. These observations indicate that the terms leaders and followers are not suited to every case. We think that it would be more accurate to dissociate the function of a cell from its position in the group. The position of cells can be precisely defined with respect to the direction of movement by purely topological terms such as “front” or “rear” cells. In addition, we propose the more ample and strictly functional definition of “steering cells” which are able to determine the directionality of movement for the entire group. In this context, a leader cell represents only a specific case in which a steering cell is positioned at the front of the group

Rôle du proto-oncogène Ets1 au cours du développement des cellules des crêtes neurales aviaires

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Neural crest streaming as an emergent property of tissue interactions during morphogenesis.

A fundamental question in embryo morphogenesis is how a complex pattern is established in seemingly uniform tissues. During vertebrate development, neural crest cells differentiate as a continuous mass of tissue along the neural tube and subsequently split into spatially distinct migratory streams to invade the rest of the embryo. How these streams are established is not well understood. Inhibitory signals surrounding the migratory streams led to the idea that position and size of streams are determined by a pre-pattern of such signals. While clear evidence for a pre-pattern in the cranial region is still lacking, all computational models of neural crest migration published so far have assumed a pre-pattern of negative signals that channel the neural crest into streams. Here we test the hypothesis that instead of following a pre-existing pattern, the cranial neural crest creates their own migratory pathway by interacting with the surrounding tissue. By combining theoretical modeling with experimentation, we show that streams emerge from the interaction of the hindbrain neural crest and the neighboring epibranchial placodal tissues, without the need for a pre-existing guidance cue. Our model suggests that the initial collective neural crest invasion is based on short-range repulsion and asymmetric attraction between neighboring tissues. The model provides a coherent explanation for the formation of cranial neural crest streams in concert with previously reported findings and our new in vivo observations. Our results point to a general mechanism of inducing collective invasion patterns

Interkinetic nuclear movements promote apical expansion in pseudostratified epithelia at the expense of apicobasal elongation.

Pseudostratified epithelia (PSE) are a common type of columnar epithelia found in a wealth of embryonic and adult tissues such as ectodermal placodes, the trachea, the ureter, the gut and the neuroepithelium. PSE are characterized by the choreographed displacement of cells' nuclei along the apicobasal axis according to phases of their cell cycle. Such movements, called interkinetic movements (INM), have been proposed to influence tissue expansion and shape and suggested as culprit in several congenital diseases such as CAKUT (Congenital anomalies of kidney and urinary tract) and esophageal atresia. INM rely on cytoskeleton dynamics just as adhesion, contractility and mitosis do. Therefore, long term impairment of INM without affecting proliferation and adhesion is currently technically unachievable. Here we bypassed this hurdle by generating a 2D agent-based model of a proliferating PSE and compared its output to the growth of the chick neuroepithelium to assess the interplay between INM and these other important cell processes during growth of a PSE. We found that INM directly generates apical expansion and apical nuclear crowding. In addition, our data strongly suggest that apicobasal elongation of cells is not an emerging property of a proliferative PSE but rather requires a specific elongation program. We then discuss how such program might functionally link INM, tissue growth and differentiation