Cell polarity and morphogenesis of epithelia
Group leader : A. Le Bivic
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.
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.
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.
February 2nd, 2018
The elmo-mbc complex and rhogap19d couple Rho family GTPases during mesenchymal-to-epithelial-like transitions.
December 1st, 2017
Crumbs, Moesin and Yurt regulate junctional stability and dynamics for a proper morphogenesis of the Drosophila pupal wing epithelium.
November 13th, 2017
Animal multicellularity and polarity without Wnt signaling.
October 16th, 2017
Role of the crumbs proteins in ciliogenesis, cell migration and actin organization.
September 14th, 2016
The PCP pathway regulates Baz planar distribution in epithelial cells.
September 14th, 2016
Hook2, a microtubule-binding protein, interacts with Par6α and controls centrosome orientation during polarized cell migration.
January 21st, 2015
The Crumbs3 complex
January 12th, 2014
Drebrin E depletion in human intestinal epithelial cells mimics Rab8a loss of function.
October 15th, 2013
The multi-PDZ domain protein-1 (MUPP-1) expression regulates cellular levels of the PALS-1/PATJ polarity complex.
September 11th, 2013
Evolution and Cell Physiology. 4. Why invent yet another protein complex to build junctions in epithelial cells?
July 7th, 2017
Binding of ZO-1 to α5β1 integrins regulates the mechanical properties of α5β1-fibronectin links.
January 17th, 2017
Quantitative methods to study epithelial morphogenesis and polarity
May 6th, 2016
P-cadherin-mediated Rho GTPase regulation during collective cell migration.
January 21st, 2016
The localisation of the apical Par/Cdc42 polarity module is specifically affected in microvillus inclusion disease.
January 16th, 2016
Segmentation and Quantitative Analysis of Epithelial Tissues.
September 3rd, 2015
Draft Genome Sequence of an Alphaproteobacterium Associated with the Mediterranean Sponge Oscarella lobularis.
July 30th, 2015
Mitochondrial Genome Sequence of the Glass Sponge Oopsacas minuta.
July 15th, 2014
CRB2 acts as a modifying factor of CRB1-related retinal dystrophies in mice.
November 27th, 2013
Targeted Ablation of Crumbs1 and Crumbs2 in Retinal Progenitor Cells Mimics Leber Congenital Amaurosis.
September 15th, 2013
Primary cilium migration depends on G-protein signalling control of subapical cytoskeleton.
January 1st, 2013