TEAM

Cell polarity and morphogenesis of epithelia

Group leader : A. Le Bivic

Presentation
Publications

Our project aims to understand the mechanisms that control the polarized organization of epithelial cells and the role of polarity complexes in the formation and maintenance of this organization. We are particularly interested in the role of the subapical cytoskeleton and in the evolution of this organization in the metazoan branch. In the long term, these studies will allow us to better understand how these mechanisms have emerged in the animal evolution and how deregulation of the epithelial layers organization is disturbed during, for example, the carcinogenesis process.

FOR BEGINNERS

Epithelia are involved in animal homeostasis by forming a barrier between the external and internal compartments. The establishment of epithelial layers requires the coordination of polarity complexes that are essential to define the apical surface in contact with the external environment and the lateral surface where intercellular junctions are positioned. In epithelial cells, the establishment of the plasma membrane specialized areas and of corresponding junctions at the border of these areas is accompanied by cytoskeletal organization of the subapical area to withstand tissue stresses and to anchor the microvilli of the apical pole. Our group investigates what molecular factors are essential for this apical organization and how polarity complexes are involved in this process. For that, we focus on the role of the Crumbs and Par6/aPKC complex in the establishment and maintenance of the apical pole in epithelial cells of the human intestine (enterocytes) and of the pupal wing Drosophila. Another aspect of the apical membrane specification is the formation of the primary cilium and many genes regulating cilia formation are also the cause of ciliopathies when mutated. The primary cilium is essential for many signalling pathways and the role of polarity complexes in its formation has been demonstrated. We thus study the role of the Crumbs and aPKC/Par6 complex in a model of epithelial cells from human retina and Xenopus embryonic ectoderm.

FOR SPECIALISTS

Our work focuses on two main issues of life science:

How epithelial structures that have led to the emergence of all multicellular animals has emerged during the evolution. This stage of evolution required the invention of new protein complexes necessary for cell cohesion and its modulation during morphogenetic movements and morphogenic signals of cell and tissue specification. The emergence of the Crumbs complex in the metazoan phylum and its functions in the organization and maintenance of epithelial junctions that emerge simultaneously (complex Cadherins) corresponds to expected complexes to pass this course of animal evolution.

The other major issue addressed byour work is the regulation of epithelial homeostasis, which is essential to animal life. This homeostasis is challenged during carcinogenic events and it should be remembered that the epithelia are responsible for 80% of cancers in adult men. It is now accepted that defects in expression or localization of polarity complexes induce disturbances of epithelial organization and are precancerous events. More generally, epithelium are privileged targets for many diseases such as cystic fibrosis or pathogens infection (viruses and bacteria).

Our group focuses on cellular and tissular causes of two diseases, either directly linked to Crumbs complex (retinitis pigmentosa) or linked to apical cytoskeletal organization (intestival microvillus inclusions). It has been shown in 1999, by the group of F. Cremers from Nimègue, that the CRB1 gene (Crumbs1) is responsible for diseases of the retina in humans, which are described under the names of Leber congenital amaurosis (LCA) and Retinitis pigmentosa type 12 (RP12). This disease has been mimicked in mice whith CRB1 gene mutation, which prove its role in this process. Our aim in the context of a collaborative research work with the group of J. Wijnholds in Amsterdam is to understand how the loss of Crumbs1 can induce retinal degeneration and how therapy can be considered in humans to prevent this degeneration. The other pathology we are studying is the microvillus inclusion disease (MID), a disease of the newborn intestine and is mainly caused by mutations in the myosin Vb, a subapical component of the cytoskeleton. In this context we study the role of Drebrin, a protein binding actin in the apical domain organization and whose depletion in human intestinal cells strongly mimics the loss of function of Myosin Vb.Drebrine is therefore a good candidate to explain the formation defects in the apical membrane in MID.

Main publications

PUBLICATION

September 14th, 2016

The PCP pathway regulates Baz planar distribution in epithelial cells.

Aigouy B, Le Bivic A.

Sci Rep. 2016 Sep 14;6:33420. PMID: 27624969

Cell polarity and morphogenesis of epithelia

Group leader : A. Le Bivic

FOR BEGINNERS

FOR SPECIALISTS

Main publications

The PCP pathway regulates Baz planar distribution in epithelial cells.

Hook2, a microtubule-binding protein, interacts with Par6α and controls centrosome orientation during polarized cell migration.

The Crumbs3 complex

Drebrin E depletion in human intestinal epithelial cells mimics Rab8a loss of function.

The multi-PDZ domain protein-1 (MUPP-1) expression regulates cellular levels of the PALS-1/PATJ polarity complex.

Evolution and Cell Physiology. 4. Why invent yet another protein complex to build junctions in epithelial cells?

Apico-basal elongation requires a drebrin-E-EB3 complex in columnar human epithelial cells.

Hook2 is involved in the morphogenesis of the primary cilium.

Crumbs proteins in epithelial morphogenesis.

Polarity complex proteins.

Evidence for a molecular link between the tuberous sclerosis complex and the Crumbs complex.

PATJ connects and stabilizes apical and lateral components of tight junctions in human intestinal cells.

E-cadherin-mediated adhesion is not the founding event of epithelial cell polarity in Drosophila.

Role of Crumbs proteins in the control of epithelial cell and photoreceptor morphogenesis

CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells.

The scaffolding domain of caveolin 2 is responsible for its Golgi localization in Caco-2 cells.

Role of the Crumbs complex in the regulation of junction formation in Drosophila and mammalian epithelial cells.

Crumbs interacts with moesin and beta(Heavy)-spectrin in the apical membrane skeleton of Drosophila.

hINADl/PATJ, a homolog of discs lost, interacts with crumbs and localizes to tight junctions in human epithelial cells.

Role of the membrane-proximal O-glycosylation site in sorting of the human receptor for neurotrophins to the apical membrane of MDCK cells.

Other publications

The localisation of the apical Par/Cdc42 polarity module is specifically affected in microvillus inclusion disease.

Draft Genome Sequence of an Alphaproteobacterium Associated with the Mediterranean Sponge Oscarella lobularis.

Mitochondrial Genome Sequence of the Glass Sponge Oopsacas minuta.

CRB2 acts as a modifying factor of CRB1-related retinal dystrophies in mice.

Targeted Ablation of Crumbs1 and Crumbs2 in Retinal Progenitor Cells Mimics Leber Congenital Amaurosis.

Primary cilium migration depends on G-protein signalling control of subapical cytoskeleton.

Loss of CRB2 in the mouse retina mimics human retinitis pigmentosa due to mutations in the CRB1 gene.

PALS1 is essential for retinal pigment epithelium structure and neural retina stratification.

Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6.

CD146 and its soluble form regulate monocyte transendothelial migration.

FERM protein EPB41L5 is a novel member of the mammalian CRB-MPP5 polarity complex.

Distinct v-SNAREs regulate direct and indirect apical delivery in polarized epithelial cells.

Role of aPKC isoforms and their binding partners Par3 and Par6 in epidermal barrier formation.

Apical sorting by galectin-3-dependent glycoprotein clustering.

Heterogeneity of Raft-type membrane microdomains associated with VP4, the rotavirus spike protein, in Caco-2 and MA 104 cells.

Pals1/Mpp5 is required for correct localization of Crb1 at the subapical region in polarized Muller glia cells.

Computer modelling in combination with in vitro studies reveals similar binding affinities of Drosophila Crumbs for the PDZ domains of Stardust and DmPar-6.

Requirement for galectin-3 in apical protein sorting.

Junctional recruitment of mammalian Scribble relies on E-cadherin engagement.

Galectin-4 and sulfatides in apical membrane trafficking in enterocyte-like cells.

Crumbs homologue 1 is required for maintenance of photoreceptor cell polarization and adhesion during light exposure.

Epithelial trafficking: new routes to familiar places.

EFA6, exchange factor for ARF6, regulates the actin cytoskeleton and associated tight junction in response to E-cadherin engagement.

Differential recognition of a tyrosine-dependent signal in the basolateral and endocytic pathways of thyroid epithelial cells.

Interaction between Erbin and a Catenin-related protein in epithelial cells.

Research

Keywords

Interactions

IBDM

NATIONAL

INTERNATIONAL

Funding

Members more

André Le Bivic

Benoît Aigouy

Veronika Aksenova

Magali Barthelemy

Elsa Bazellieres

Céline Burckle

Dominique Massey Harroche

Juliette Raitiere

Christopher Toret

Alumni

Overview

Model organism

Biological process studied

Medical applications