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.