Publications by authors named "Mehdi Saadaoui"

11 Publications

  • Page 1 of 1

A tensile ring drives tissue flows to shape the gastrulating amniote embryo.

Science 2020 01;367(6476):453-458

Department of Developmental and Stem Cell Biology Institut Pasteur, 75724 Paris, Cedex 15, France.

Tissue morphogenesis is driven by local cellular deformations that are powered by contractile actomyosin networks. How localized forces are transmitted across tissues to shape them at a mesoscopic scale is still unclear. Analyzing gastrulation in entire avian embryos, we show that it is driven by the graded contraction of a large-scale supracellular actomyosin ring at the margin between the embryonic and extraembryonic territories. The propagation of these forces is enabled by a fluid-like response of the epithelial embryonic disk, which depends on cell division. A simple model of fluid motion entrained by a tensile ring quantitatively captures the vortex-like "polonaise" movements that accompany the formation of the primitive streak. The geometry of the early embryo thus arises from the transmission of active forces generated along its boundary.
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http://dx.doi.org/10.1126/science.aaw1965DOI Listing
January 2020

Experimental validation of force inference in epithelia from cell to tissue scale.

Sci Rep 2019 10 10;9(1):14647. Epub 2019 Oct 10.

Aix Marseille Univ, CNRS, IBDM, Turing Center for Living Systems, Marseille, France.

Morphogenesis relies on the active generation of forces, and the transmission of these forces to surrounding cells and tissues. Hence measuring forces directly in developing embryos is an essential task to study the mechanics of development. Among the experimental techniques that have emerged to measure forces in epithelial tissues, force inference is particularly appealing. Indeed it only requires a snapshot of the tissue, as it relies on the topology and geometry of cell contacts, assuming that forces are balanced at each vertex. However, establishing force inference as a reliable technique requires thorough validation in multiple conditions. Here we performed systematic comparisons of force inference with laser ablation experiments in four epithelial tissues from two animals, the fruit fly and the quail. We show that force inference accurately predicts single junction tension, tension patterns in stereotyped groups of cells, and tissue-scale stress patterns, in wild type and mutant conditions. We emphasize its ability to capture the distribution of forces at different scales from a single image, which gives it a critical advantage over perturbative techniques such as laser ablation. Overall, our results demonstrate that force inference is a reliable and efficient method to quantify the mechanical state of epithelia during morphogenesis, especially at larger scales when inferred tensions and pressures are binned into a coarse-grained stress tensor.
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http://dx.doi.org/10.1038/s41598-019-50690-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787039PMC
October 2019

Loss of the canonical spindle orientation function in the Pins/LGN homolog AGS3.

EMBO Rep 2017 09 6;18(9):1509-1520. Epub 2017 Jul 6.

Cell Division and Neurogenesis Group, Ecole Normale Supérieure, CNRS, Inserm, Institut de Biologie de l'Ecole Normale Supérieure (IBENS), PSL Research University, Paris, France

In many cell types, mitotic spindle orientation relies on the canonical "LGN complex" composed of Pins/LGN, Mud/NuMA, and Gα subunits. Membrane localization of this complex recruits motor force generators that pull on astral microtubules to orient the spindle. Pins shares highly conserved functional domains with its two vertebrate homologs LGN and AGS3. Whereas the role of Pins and LGN in oriented divisions is extensively documented, involvement of AGS3 remains controversial. Here, we show that AGS3 is not required for planar divisions of neural progenitors in the mouse neocortex. AGS3 is not recruited to the cell cortex and does not rescue LGN loss of function. Despite conserved interactions with NuMA and Gα, comparison of LGN and AGS3 functional domains reveals unexpected differences in the ability of these interactions to mediate spindle orientation functions. Finally, we find that Pins is unable to substitute for LGN loss of function in vertebrates, highlighting that species-specific modulations of the interactions between components of the Pins/LGN complex are crucial for spindle orientation.
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http://dx.doi.org/10.15252/embr.201643048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579374PMC
September 2017

Cell Division Drives Epithelial Cell Rearrangements during Gastrulation in Chick.

Dev Cell 2016 Feb;36(3):249-61

Department of Developmental and Stem Cell Biology, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France; CNRS URA2578, rue du Dr Roux, 75015 Paris, France. Electronic address:

During early embryonic development, cells are organized as cohesive epithelial sheets that are continuously growing and remodeled without losing their integrity, giving rise to a wide array of tissue shapes. Here, using live imaging in chick embryo, we investigate how epithelial cells rearrange during gastrulation. We find that cell division is a major rearrangement driver that powers dramatic epithelial cell intercalation events. We show that these cell division-mediated intercalations, which represent the majority of epithelial rearrangements within the early embryo, are absolutely necessary for the spatial patterning of gastrulation movements. Furthermore, we demonstrate that these intercalation events result from overall low cortical actomyosin accumulation within the epithelial cells of the embryo, which enables dividing cells to remodel junctions in their vicinity. These findings uncover a role for cell division as coordinator of epithelial growth and remodeling that might underlie various developmental, homeostatic, or pathological processes in amniotes.
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http://dx.doi.org/10.1016/j.devcel.2016.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485541PMC
February 2016

A survey of conservation of sea spider and Drosophila Hox protein activities.

Mech Dev 2015 Nov 1;138 Pt 2:73-86. Epub 2015 Aug 1.

Aix Marseille Université, CNRS, IBDM, UMR 7288, Campus de Luminy, Marseille, cedex 09 13288, France.

Hox proteins have well-established functions in development and evolution, controlling the final morphology of bilaterian animals. The common phylogenetic origin of Hox proteins and the associated evolutionary diversification of protein sequences provide a unique framework to explore the relationship between changes in protein sequence and function. In this study, we aimed at questioning how sequence variation within arthropod Hox proteins influences function. This was achieved by exploring the functional impact of sequence conservation/divergence of the Hox genes, labial, Sex comb reduced, Deformed, Ultrabithorax and abdominalA from two distant arthropods, the sea spider and the well-studied Drosophila. Results highlight a correlation between sequence conservation within the homeodomain and the degree of functional conservation, and identify a novel functional domain in the Labial protein.
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http://dx.doi.org/10.1016/j.mod.2015.07.010DOI Listing
November 2015

Dlg1 controls planar spindle orientation in the neuroepithelium through direct interaction with LGN.

J Cell Biol 2014 Sep 8;206(6):707-17. Epub 2014 Sep 8.

Institut de Biologie de l'École Normale Supérieure, Ecole Normale Supérieure, F-75005 Paris, France Institut National de la Santé et de la Recherche Medicale, U1024, F-75005 Paris, France Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8197, F-75005 Paris, France

Oriented cell divisions are necessary for the development of epithelial structures. Mitotic spindle orientation requires the precise localization of force generators at the cell cortex via the evolutionarily conserved LGN complex. However, polarity cues acting upstream of this complex in vivo in the vertebrate epithelia remain unknown. In this paper, we show that Dlg1 is localized at the basolateral cell cortex during mitosis and is necessary for planar spindle orientation in the chick neuroepithelium. Live imaging revealed that Dlg1 is required for directed spindle movements during metaphase. Mechanistically, we show that direct interaction between Dlg1 and LGN promotes cortical localization of the LGN complex. Furthermore, in human cells dividing on adhesive micropatterns, homogenously localized Dlg1 recruited LGN to the mitotic cortex and was also necessary for proper spindle orientation. We propose that Dlg1 acts primarily to recruit LGN to the cortex and that Dlg1 localization may additionally provide instructive cues for spindle orientation.
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http://dx.doi.org/10.1083/jcb.201405060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164945PMC
September 2014

Insights into Hox protein function from a large scale combinatorial analysis of protein domains.

PLoS Genet 2011 Oct 27;7(10):e1002302. Epub 2011 Oct 27.

Institut de Biologie du Développement de Marseille Luminy, UMR6216 CNRS, Parc Scientifique de Luminy, Case 907, Marseille, France.

Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA), we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences.
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http://dx.doi.org/10.1371/journal.pgen.1002302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203194PMC
October 2011

A lateral belt of cortical LGN and NuMA guides mitotic spindle movements and planar division in neuroepithelial cells.

J Cell Biol 2011 Apr 28;193(1):141-54. Epub 2011 Mar 28.

Université de la Méditerranée/Aix-Marseille II, Developmental Biology Institute (IBDML), Centre National de la Recherche Scientifique UMR6216, Case 907, Campus de Luminy, 13288 Marseille, France.

To maintain tissue architecture, epithelial cells divide in a planar fashion, perpendicular to their main polarity axis. As the centrosome resumes an apical localization in interphase, planar spindle orientation is reset at each cell cycle. We used three-dimensional live imaging of GFP-labeled centrosomes to investigate the dynamics of spindle orientation in chick neuroepithelial cells. The mitotic spindle displays stereotypic movements during metaphase, with an active phase of planar orientation and a subsequent phase of planar maintenance before anaphase. We describe the localization of the NuMA and LGN proteins in a belt at the lateral cell cortex during spindle orientation. Finally, we show that the complex formed of LGN, NuMA, and of cortically located Gαi subunits is necessary for spindle movements and regulates the dynamics of spindle orientation. The restricted localization of LGN and NuMA in the lateral belt is instructive for the planar alignment of the mitotic spindle, and required for its planar maintenance.
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http://dx.doi.org/10.1083/jcb.201101039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082188PMC
April 2011

Selection of distinct Hox-Extradenticle interaction modes fine-tunes Hox protein activity.

Proc Natl Acad Sci U S A 2011 Feb 24;108(6):2276-81. Epub 2011 Jan 24.

Institut de Biologie du Développement de Marseille Luminy, Centre National de la Recherche Scientifique, Université de la Méditerranée, 13288 Marseille Cedex 09, France.

Hox genes encode transcription factors widely used for diversifying animal body plans in development and evolution. To achieve functional specificity, Hox proteins associate with PBC class proteins, Pre-B cell leukemia homeobox (Pbx) in vertebrates, and Extradenticle (Exd) in Drosophila, and were thought to use a unique hexapeptide-dependent generic mode of interaction. Recent findings, however, revealed the existence of an alternative, UbdA-dependent paralog-specific interaction mode providing diversity in Hox-PBC interactions. In this study, we investigated the basis for the selection of one of these two Hox-PBC interaction modes. Using naturally occurring variations and mutations in the Drosophila Ultrabithorax protein, we found that the linker region, a short domain separating the hexapeptide from the homeodomain, promotes an interaction mediated by the UbdA domain in a context-dependent manner. While using a UbdA-dependent interaction for the repression of the limb-promoting gene Distalless, interaction with Exd during segment-identity specification still relies on the hexapeptide motif. We further show that distinctly assembled Hox-PBC complexes display subtle but distinct repressive activities. These findings identify Hox-PBC interaction as a template for subtle regulation of Hox protein activity that may have played a major role in the diversification of Hox protein function in development and evolution.
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http://dx.doi.org/10.1073/pnas.1006964108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038764PMC
February 2011

Classification of sequence signatures: a guide to Hox protein function.

Bioessays 2009 May;31(5):500-11

Institut de Biologie du Développement de Marseille Luminy, IBDML, UMR 6216, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907, Marseille Cedex 09, France.

Hox proteins are part of the conserved superfamily of homeodomain-containing transcription factors and play fundamental roles in shaping animal body plans in development and evolution. However, molecular mechanisms underlying their diverse and specific biological functions remain largely enigmatic. Here, we have analyzed Hox sequences from the main evolutionary branches of the Bilateria group. We have found that four classes of Hox protein signatures exist, which together provide sufficient support to explain how different Hox proteins differ in their control and function. The homeodomain and its surrounding sequences accumulate nearly all signatures, constituting an extended module where most of the information distinguishing Hox proteins is concentrated. Only a small fraction of these signatures has been investigated at the functional level, but these show that approaches relying on Hox protein alterations still have a large potential for deciphering molecular mechanisms of Hox differential control.
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http://dx.doi.org/10.1002/bies.200800229DOI Listing
May 2009

A unique Extradenticle recruitment mode in the Drosophila Hox protein Ultrabithorax.

Proc Natl Acad Sci U S A 2007 Oct 17;104(43):16946-51. Epub 2007 Oct 17.

Institut de Biologie du Développement de Marseille Luminy, Centre National de la Recherche Scientifique, Université de la Méditerranée, Parc Scientifique de Luminy, 13288 Marseille Cedex 09, France.

Hox transcription factors are essential for shaping body morphology in development and evolution. The control of Hox protein activity in part arises from interaction with the PBC class of partners, pre-B cell transcription factor (Pbx) proteins in vertebrates and Extradenticle (Exd) in Drosophila. Characterized interactions occur through a single mode, involving a short hexapeptide motif in the Hox protein. This apparent uniqueness in Hox-PBC interaction provides little mechanistic insight in how the same cofactors endow Hox proteins with specific and diverse activities. Here, we identify in the Drosophila Ultrabithorax (Ubx) protein a short motif responsible for an alternative mode of Exd recruitment. Together with previous reports, this finding highlights that the Hox protein Ubx has multiple ways to interact with the Exd cofactor and suggests that flexibility in Hox-PBC contacts contributes to specify and diversify Hox protein function.
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http://dx.doi.org/10.1073/pnas.0705832104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2040397PMC
October 2007
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