Polarité, division et morphogenèse

Publications de l’équipe

Année de publication : 2013

Joffrey L Degoutin, Claire C Milton, Eefang Yu, Marla Tipping, Floris Bosveld, Liu Yang, Yohanns Bellaiche, Alexey Veraksa, Kieran F Harvey (2013 Aug 20)

Riquiqui and minibrain are regulators of the hippo pathway downstream of Dachsous.

Nature cell biology : 1176-85 : DOI : 10.1038/ncb2829 En savoir plus
Résumé

The atypical cadherins Fat (Ft) and Dachsous (Ds) control tissue growth through the Salvador-Warts-Hippo (SWH) pathway, and also regulate planar cell polarity and morphogenesis. Ft and Ds engage in reciprocal signalling as both proteins can serve as receptor and ligand for each other. The intracellular domains (ICDs) of Ft and Ds regulate the activity of the key SWH pathway transcriptional co-activator protein Yorkie (Yki). Signalling from the FtICD is well characterized and controls tissue growth by regulating the abundance of the Yki-repressive kinase Warts (Wts). Here we identify two regulators of the Drosophila melanogaster SWH pathway that function downstream of the DsICD: the WD40 repeat protein Riquiqui (Riq) and the DYRK-family kinase Minibrain (Mnb). Ds physically interacts with Riq, which binds to both Mnb and Wts. Riq and Mnb promote Yki-dependent tissue growth by stimulating phosphorylation-dependent inhibition of Wts. Thus, we describe a previously unknown branch of the SWH pathway that controls tissue growth downstream of Ds.

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Bertrand Jauffred, Flora Llense, Bernhard Sommer, Zhimin Wang, Charlotte Martin, Yohanns Bellaïche (2013 May 31)

Regulation of centrosome movements by numb and the collapsin response mediator protein during Drosophila sensory progenitor asymmetric division.

Development (Cambridge, England) : 2657-68 : DOI : 10.1242/dev.087338 En savoir plus
Résumé

Asymmetric cell division generates cell fate diversity during development and adult life. Recent findings have demonstrated that during stem cell divisions, the movement of centrosomes is asymmetric in prophase and that such asymmetry participates in mitotic spindle orientation and cell polarization. Here, we have investigated the dynamics of centrosomes during Drosophila sensory organ precursor asymmetric divisions and find that centrosome movements are asymmetric during cytokinesis. We demonstrate that centrosome movements are controlled by the cell fate determinant Numb, which does not act via its classical effectors, Sanpodo and α-Adaptin, but via the Collapsin Response Mediator Protein (CRMP). Furthermore, we find that CRMP is necessary for efficient Notch signalling and that it regulates the duration of the pericentriolar accumulation of Rab11-positive endosomes, through which the Notch ligand, Delta is recycled. Our work characterizes an additional mode of asymmetric centrosome movement during asymmetric divisions and suggests a model whereby the asymmetry in centrosome movements participates in differential Notch activation to regulate cell fate specification.

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Pierre-Luc Bardet, Boris Guirao, Camille Paoletti, Fanny Serman, Valentine Léopold, Floris Bosveld, Yûki Goya, Vincent Mirouse, François Graner, Yohanns Bellaïche (2013 May 28)

PTEN controls junction lengthening and stability during cell rearrangement in epithelial tissue.

Developmental cell : 534-46 : DOI : 10.1016/j.devcel.2013.04.020 En savoir plus
Résumé

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.

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Carl-Philipp Heisenberg, Yohanns Bellaïche (2013 May 28)

Forces in tissue morphogenesis and patterning.

Cell : 948-62 : DOI : 10.1016/j.cell.2013.05.008 En savoir plus
Résumé

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.

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Shuji Ishihara, Kaoru Sugimura, Simon J. Cox, Isabelle Bonnet, Yohanns Bellaïche, François Graner (2013 Apr 26)

Comparative study of non-invasive force and stress inference methods in tissue.

The European physical journal. E, Soft matter : 9859 : DOI : 10.1140/epje/i2013-13045-8 En savoir plus
Résumé

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.

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F Etoc, D Lisse, Y Bellaiche, J Piehler, M Coppey, M Dahan (2013 Mar 5)

Subcellular control of Rac-GTPase signalling by magnetogenetic manipulation inside living cells.

Nature nanotechnology : 193-8 : DOI : 10.1038/nnano.2013.23 En savoir plus
Résumé

Many cell functions rely on the coordinated activity of signalling pathways at a subcellular scale. However, there are few tools capable of probing and perturbing signalling networks with a spatial resolution matching the intracellular dimensions of their activity patterns. Here we present a generic magnetogenetic approach based on the self-assembly of signalling complexes on the surface of functionalized magnetic nanoparticles inside living cells. The nanoparticles act as nanoscopic hot spots that can be displaced by magnetic forces and trigger signal transduction pathways that bring about a cell response. We applied this strategy to Rho-GTPases, a set of molecular switches known to regulate cell morphology via complex spatiotemporal patterns of activity. We demonstrate that the nanoparticle-mediated activation of signalling pathways leads to local remodelling of the actin cytoskeleton and to morphological changes.

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Sophie Herszterg, Andrea Leibfried, Floris Bosveld, Charlotte Martin, Yohanns Bellaiche (2013 Feb 16)

Interplay between the dividing cell and its neighbors regulates adherens junction formation during cytokinesis in epithelial tissue.

Developmental cell : 256-70 : DOI : 10.1016/j.devcel.2012.11.019 En savoir plus
Résumé

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.

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Année de publication : 2012

Floris Bosveld, Isabelle Bonnet, Boris Guirao, Sham Tlili, Zhimin Wang, Ambre Petitalot, Raphaël Marchand, Pierre-Luc Bardet, Philippe Marcq, François Graner, Yohanns Bellaïche (2012 Apr 14)

Mechanical control of morphogenesis by Fat/Dachsous/Four-jointed planar cell polarity pathway.

Science (New York, N.Y.) : 724-7 : DOI : 10.1126/science.1221071 En savoir plus
Résumé

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.

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Bertrand Jauffred, Yohanns Bellaiche (2012 Jan 6)

Analyzing frizzled signaling using fixed and live imaging of the asymmetric cell division of the Drosophila sensory organ precursor cell.

Methods in molecular biology (Clifton, N.J.) : 19-25 : DOI : 10.1007/978-1-61779-510-7_2 En savoir plus
Résumé

When you look at the dorsal thorax of a fruitfly, you can easily get fascinated by the high degree of alignment of the bristles that show a strong polarization in their surface organization. This organization of cells in the plane of the epithelium is known as planar cell polarity (PCP), and was initially characterized in Drosophila melanogaster. This process is important in a broad variety of morphological cellular asymmetries in various organisms. In Drosophila, genetic studies of PCP mutants showed that the asymmetric division of the sensory organ precursor cell (pI cell) is polarized along the anterior-posterior axis by Frizzled receptor signaling. Here, we described two methods to image and analyze the PCP in the pI cell model.

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Année de publication : 2011

Xavier Morin, Yohanns Bellaïche (2011 Jul 19)

Mitotic spindle orientation in asymmetric and symmetric cell divisions during animal development.

Developmental cell : 102-19 : DOI : 10.1016/j.devcel.2011.06.012 En savoir plus
Résumé

The orientation of the mitotic spindle has been proposed to control cell fate choices, tissue architecture, and tissue morphogenesis. Here, we review the mechanisms regulating the orientation of the axis of division and cell fate choices in classical models of asymmetric cell division. We then discuss the mechanisms of mitotic spindle orientation in symmetric cell divisions and its possible implications in tissue morphogenesis. Many recent studies show that future advances in the field of mitotic spindle orientation will arise from combinations of physical perturbation and modeling with classical genetics and developmental biology approaches.

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Année de publication : 2010

Juliette D Godin, Kelly Colombo, Maria Molina-Calavita, Guy Keryer, Diana Zala, Bénédicte C Charrin, Paula Dietrich, Marie-Laure Volvert, François Guillemot, Ioannis Dragatsis, Yohanns Bellaiche, Frédéric Saudou, Laurent Nguyen, Sandrine Humbert (2010 Aug 11)

Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis.

Neuron : 392-406 : DOI : 10.1016/j.neuron.2010.06.027 En savoir plus
Résumé

Huntingtin is the protein mutated in Huntington’s disease, a devastating neurodegenerative disorder. We demonstrate here that huntingtin is essential to control mitosis. Huntingtin is localized at spindle poles during mitosis. RNAi-mediated silencing of huntingtin in cells disrupts spindle orientation by mislocalizing the p150(Glued) subunit of dynactin, dynein, and the large nuclear mitotic apparatus NuMA protein. This leads to increased apoptosis following mitosis of adherent cells in vitro. In vivo inactivation of huntingtin by RNAi or by ablation of the Hdh gene affects spindle orientation and cell fate of cortical progenitors of the ventricular zone in mouse embryos. This function is conserved in Drosophila, the specific disruption of Drosophila huntingtin in neuroblast precursors leading to spindle misorientation. Moreover, Drosophila huntingtin restores spindle misorientation in mammalian cells. These findings reveal an unexpected role for huntingtin in dividing cells, with potential important implications in health and disease.

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Marion Ségalen, Christopher A Johnston, Charlotte A Martin, Julien G Dumortier, Kenneth E Prehoda, Nicolas B David, Chris Q Doe, Yohanns Bellaïche (2010 Apr 19)

The Fz-Dsh planar cell polarity pathway induces oriented cell division via Mud/NuMA in Drosophila and zebrafish.

Developmental cell : 740-52 : DOI : 10.1016/j.devcel.2010.10.004 En savoir plus
Résumé

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.

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Maria-Isabel Yuseff, Anne Reversat, Danielle Lankar, Jheimmy Diaz, Isabelle Fanget, Paolo Pierobon, Violaine Randrian, Nathanael Larochette, Fulvia Vascotto, Chantal Desdouets, Bertrand Jauffred, Yohanns Bellaiche, Stéphane Gasman, François Darchen, Claire Desnos, Ana-Maria Lennon-Duménil (2010 Mar 11)

Polarized secretion of lysosomes at the B cell synapse couples antigen extraction to processing and presentation.

Immunity : 361-74 : DOI : 10.1016/j.immuni.2011.07.008 En savoir plus
Résumé

Engagement of the B cell receptor (BCR) by surface-tethered antigens (Ag) leads to formation of a synapse that promotes Ag uptake for presentation onto major histocompatibility complex class II (MHCII) molecules. We have highlighted the membrane trafficking events and associated molecular mechanisms involved in Ag extraction and processing at the B cell synapse. MHCII-containing lysosomes are recruited to the synapse where they locally undergo exocytosis, allowing synapse acidification and the extracellular release of hydrolases that promote the extraction of the immobilized Ag. Lysosome recruitment and secretion results from the polarization of the microtubule-organizing center (MTOC), which relies on the cell division cycle (Cdc42)-downstream effector, atypical protein kinase C (aPKCζ). aPKCζ is phosphorylated upon BCR engagement, associates to lysosomal vesicles, and is required for their polarized secretion at the B cell synapse. Regulation of B lymphocyte polarity therefore emerges as a central mechanism that couples Ag extraction to Ag processing and presentation.

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Année de publication : 2008

Pierre Fichelson, Clara Moch, Kenzo Ivanovitch, Charlotte Martin, Clara M Sidor, Jean-Antoine Lepesant, Yohanns Bellaiche, Jean-René Huynh (2008 Nov 14)

Live-imaging of single stem cells within their niche reveals that a U3snoRNP component segregates asymmetrically and is required for self-renewal in Drosophila.

Nature cell biology : 685-93 : DOI : 10.1038/ncb1874 En savoir plus
Résumé

Stem cells generate self-renewing and differentiating progeny over many rounds of asymmetric divisions. How stem cell growth rate and size are maintained over time remains unknown. We isolated mutations in a Drosophila melanogaster gene, wicked (wcd), which induce premature differentiation of germline stem cells (GSCs). Wcd is a member of the U3 snoRNP complex required for pre-ribosomal RNA maturation. This general function of Wcd contrasts with its specific requirement for GSC self-renewal. However, live imaging of GSCs within their niche revealed a pool of Wcd-forming particles that segregate asymmetrically into the GSCs on mitosis, independently of the Dpp signal sent by the niche. A fraction of Wcd also segregated asymmetrically in dividing larval neural stem cells (NSCs). In the absence of Wcd, NSCs became smaller and produced fewer neurons. Our results show that regulation of ribosome synthesis is a crucial parameter for stem cell maintenance and function.

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Andrea Leibfried, Robert Fricke, Matthew J Morgan, Sven Bogdan, Yohanns Bellaiche (2008 Nov 4)

Drosophila Cip4 and WASp define a branch of the Cdc42-Par6-aPKC pathway regulating E-cadherin endocytosis.

Current biology : CB : 1639-48 : DOI : 10.1016/j.cub.2008.09.063 En savoir plus
Résumé

Integral to the function and morphology of the epithelium is the lattice of cell-cell junctions known as adherens junctions (AJs). AJ stability and plasticity relies on E-Cadherin exocytosis and endocytosis. A mechanism regulating E-Cadherin (E-Cad) exocytosis to the AJs has implicated proteins of the exocyst complex, but mechanisms regulating E-Cad endocytosis from the AJs remain less well understood.

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