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Polarité, division et morphogenèse

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Chef d'équipe : Yohanns Bellaïche
Equipe Yohanns Bellaïche

Mots-clés

polarité cellulaire, division, orientation du fuseau mitotique, division cellulaire asymétrique, morphogenèse

En bref

Comprendre la morphogenèse des tissus reste un des défis majeurs de la biologie moderne. Nous utilisons des approches complémentaires d’imagerie du vivant et de génétique ainsi que des outils quantitatifs nouveaux et la modélisation pour comprendre comment des mouvements de milliers de cellules peuvent être coordonnés pour que des tissus de formes données émergent au cours du développement.  Nos travaux devraient au cours des prochaines années aboutir à une vision intégrée des mécanismes de morphogenèse dont la dérégulation est observée dans diverses pathologies. 

 

 

 

 

 

 

 

 

 

 

Bourse doctorale dans le cadre du réseau ITN PolarNet

La compréhension des mécanismes de contrôle de la forme des organes ou des tissus est un enjeu central de la biologie du développement moderne. L’acquisition d’une forme (morphogenèse des tissus) émerge des mouvements collectifs des cellules au cours du développement. Comprendre la morphogenèse suppose d’identifier à la fois les mécanismes biochimiques et mécaniques qui gouvernent ces mouvements cellulaires (Heisenberg et Bellaiche, Cell, 2013). Nous avons récemment développé un nouveau modèle d’étude de la morphogenèse des tissue épithéliaux prolifératifs (Bosvled et al., Science 2012). En utilisant des approches complémentaires (génétique, l’imagerie du vivant à haute résolution, l’opto-génétique, mesures quantitative avancées, modélisation physique) nos travaux ont pour objectifs principaux de :

1.    Disséquer les mécanismes moléculaires qui contrôlent la polarité épithéliale et l’orientation du fuseau mitotique au cours des divisions. (figure 1)

2.    Lier  l’organisation du cytosquelette de la cellule, les mouvements cellulaires et les déformations des tissus à grandes échelles. (figure 2)

3.    Déterminer comment les profils d’expression géniques peuvent contrôler les mouvements distincts observés au cours de la morphogenèse.

Nos travaux devraient aboutir à une vision nouvelle et intégrée des mécanismes de morphogenèse grâce à nos études à différentes échelle de taille (sub-cellulaire, cellulaire et tissulaire) et à différentes échelles de temps (dizaines de secondes à l’heure) en s’attachant à comprendre ces processus tant du point de vue mécanique que du point de vue moléculaire.

 

figure 1 : Cytocinèse d’une cellule épithéliale (Herszterg et al., Dev Cell 2013)figure 1 : Cytocinèse d’une cellule épithéliale (Herszterg et al., Dev Cell 2013)                         

figure 2 : Prolifération au sein de l’épithélium du thorax  (Bosveled et al., Science 2012).figure 2 : Prolifération au sein de l’épithélium du thorax (Bosveled et al., Science 2012).

Publications clés

  • Année de publication : 2016

  • The orientation of cell division along the long axis of the interphase cell--the century-old Hertwig's rule--has profound roles in tissue proliferation, morphogenesis, architecture and mechanics. In epithelial tissues, the shape of the interphase cell is influenced by cell adhesion, mechanical stress, neighbour topology, and planar polarity pathways. At mitosis, epithelial cells usually adopt a rounded shape to ensure faithful chromosome segregation and to promote morphogenesis. The mechanisms underlying interphase cell shape sensing in tissues are therefore unknown. Here we show that in Drosophila epithelia, tricellular junctions (TCJs) localize force generators, pulling on astral microtubules and orienting cell division via the Dynein-associated protein Mud independently of the classical Pins/Gαi pathway. Moreover, as cells round up during mitosis, TCJs serve as spatial landmarks, encoding information about interphase cell shape anisotropy to orient division in the rounded mitotic cell. Finally, experimental and simulation data show that shape and mechanical strain sensing by the TCJs emerge from a general geometric property of TCJ distributions in epithelial tissues. Thus, in addition to their function as epithelial barrier structures, TCJs serve as polarity cues promoting geometry and mechanical sensing in epithelial tissues.
  • Année de publication : 2015

  • Understanding the mechanisms regulating development requires a quantitative characterization of cell divisions, rearrangements, cell size and shape changes, and apoptoses. We developed a multiscale formalism that relates the characterizations of each cell process to tissue growth and morphogenesis. Having validated the formalism on computer simulations, we quantified separately all morphogenetic events in the Drosophila dorsal thorax and wing pupal epithelia to obtain comprehensive statistical maps linking cell and tissue scale dynamics. While globally cell shape changes, rearrangements and divisions all significantly participate in tissue morphogenesis, locally, their relative participations display major variations in space and time. By blocking division we analyzed the impact of division on rearrangements, cell shape changes and tissue morphogenesis. Finally, by combining the formalism with mechanical stress measurement, we evidenced unexpected interplays between patterns of tissue elongation, cell division and stress. Our formalism provides a novel and rigorous approach to uncover mechanisms governing tissue development.
  • Année de publication : 2013

  • During development, mechanical forces cause changes in size, shape, number, position, and gene expression of cells. They are therefore integral to any morphogenetic processes. Force generation by actin-myosin networks and force transmission through adhesive complexes are two self-organizing phenomena driving tissue morphogenesis. Coordination and integration of forces by long-range force transmission and mechanosensing of cells within tissues produce large-scale tissue shape changes. Extrinsic mechanical forces also control tissue patterning by modulating cell fate specification and differentiation. Thus, the interplay between tissue mechanics and biochemical signaling orchestrates tissue morphogenesis and patterning in development.
  • Planar cell rearrangements control epithelial tissue morphogenesis and cellular pattern formation. They lead to the formation of new junctions whose length and stability determine the cellular pattern of tissues. Here, we show that during Drosophila wing development the loss of the tumor suppressor PTEN disrupts cell rearrangements by preventing the lengthening of newly formed junctions that become unstable and keep on rearranging. We demonstrate that the failure to lengthen and to stabilize is caused by the lack of a decrease of Myosin II and Rho-kinase concentration at the newly formed junctions. This defect results in a heterogeneous cortical contractility at cell junctions that disrupts regular hexagonal pattern formation. By identifying PTEN as a specific regulator of junction lengthening and stability, our results uncover how a homogenous distribution of cortical contractility along the cell cortex is restored during cell rearrangement to control the formation of epithelial cellular pattern.
  • How adherens junctions (AJs) are formed upon cell division is largely unexplored. Here, we found that AJ formation is coordinated with cytokinesis and relies on an interplay between the dividing cell and its neighbors. During contraction of the cytokinetic ring, the neighboring cells locally accumulate Myosin II and produce the cortical tension necessary to set the initial geometry of the daughter cell interface. However, the neighboring cell membranes impede AJ formation. Upon midbody formation and concomitantly to neighboring cell withdrawal, Arp2/3-dependent actin polymerization oriented by the midbody maintains AJ geometry and regulates AJ final length and the epithelial cell arrangement upon division. We propose that cytokinesis in epithelia is a multicellular process, whereby the cooperative actions of the dividing cell and its neighbors define a two-tiered mechanism that spatially and temporally controls AJ formation while maintaining tissue cohesiveness.
  • In the course of animal development, the shape of tissue emerges in part from mechanical and biochemical interactions between cells. Measuring stress in tissue is essential for studying morphogenesis and its physical constraints. For that purpose, a possible new approach is force inference (up to a single prefactor) from cell shapes and connectivity. It is non-invasive and can provide space-time maps of stress in a whole tissue, unlike existing methods. To validate this approach, three force-inference methods, which differ in their approach of treating indefiniteness in an inverse problem between cell shapes and forces, were compared. Tests using two artificial and two experimental data sets consistently indicate that our Bayesian force inference, by which cell-junction tensions and cell pressures are simultaneously estimated, performs best in terms of accuracy and robustness. Moreover, by measuring the stress anisotropy and relaxation, we cross-validated the force inference and the global annular ablation of tissue, each of which relies on different prefactors. A practical choice of force-inference methods in different systems of interest is discussed.
  • Année de publication : 2012

  • During animal development, several planar cell polarity (PCP) pathways control tissue shape by coordinating collective cell behavior. Here, we characterize by means of multiscale imaging epithelium morphogenesis in the Drosophila dorsal thorax and show how the Fat/Dachsous/Four-jointed PCP pathway controls morphogenesis. We found that the proto-cadherin Dachsous is polarized within a domain of its tissue-wide expression gradient. Furthermore, Dachsous polarizes the myosin Dachs, which in turn promotes anisotropy of junction tension. By combining physical modeling with quantitative image analyses, we determined that this tension anisotropy defines the pattern of local tissue contraction that contributes to shaping the epithelium mainly via oriented cell rearrangements. Our results establish how tissue planar polarization coordinates the local changes of cell mechanical properties to control tissue morphogenesis.
  • Année de publication : 2010

  • The Frizzled receptor and Dishevelled effector regulate mitotic spindle orientation in both vertebrates and invertebrates, but how Dishevelled orients the mitotic spindle is unknown. Using the Drosophila S2 cell "induced polarity" system, we find that Dishevelled cortical polarity is sufficient to orient the spindle and that Dishevelled's DEP domain mediates this function. This domain binds a C-terminal domain of Mud (the Drosophila NuMA ortholog), and Mud is required for Dishevelled-mediated spindle orientation. In Drosophila, Frizzled-Dishevelled planar cell polarity (PCP) orients the sensory organ precursor (pI) spindle along the anterior-posterior axis. We show that Dishevelled and Mud colocalize at the posterior cortex of pI, Mud localization at the posterior cortex requires Dsh, and Mud loss-of-function randomizes spindle orientation. During zebrafish gastrulation, the Wnt11-Frizzled-Dishevelled PCP pathway orients spindles along the animal-vegetal axis, and reducing NuMA levels disrupts spindle orientation. Overall, we describe a Frizzled-Dishevelled-NuMA pathway that orients division from Drosophila to vertebrates.