Morphogenesis and intracellular signalling

Keywords: signaling pathways, carcinogenesis, endocytosis, cell migration, actin cytoskeleton, epithelial cells

Besides their function specific to their tissue origin, all epithelia form a barrier between two compartments. The constitution of this selective barrier requires the formation of specialized domains of the plasma membrane. Membrane traffic, actin cytoskeleton dynamics and signal transmission all play a major role in the formation and maintenance of these domains. Our group's aim is to gain an understanding of the role of these processes in normal or pathological epithelium function.
We focus on 4 research fields:

Involvement of myosins in membrane traffic

E. Coudrier and co-workers are studying how the molecular motors (myosins, kinesins and dynein) contribute to intracellular traffic along the endocytic route and during melanosome biogenesis. For this purpose, an in vitro microtubule- or actin -dependent endosome and melanosome mobility test has been developed.

Movie 1: movement of a magnetic endosome on a fluorescent microtubule.

Movie 2: movement of a melanosome on actin filaments.

The role of fascin in colorectal cancer

D. Vignjevic and co-workers are studying the mechanisms underlying metastasis formation in colorectal cancer. By acquiring migratory capacity, certain cells escape the primary tumour to invade other organs, forming metastases. We are interested in the role of fascin, a protein involved in organising networks of actin bundles, in the formation of protrusive membrane structures - filopods and invadopods -, which break down the extracellular matrix, thus creating a passage for cell migration. We use biochemical techniques to search for partners regulating fascin activation, along with advanced imaging technics to view cell migration, particularly in vivo for understanding which steps in the metastatic process are fascin-regulated.

The role of ezrin in epithelial cell morphogenesis

M. Arpin and co-workers are analysing the role of the membrane-cytoskeleton linker, ezrin, in epithelial cell morphogenesis. In response to signals from the cell' environment, this protein coordinates actin filament dynamics, along with the transport/regulation of membrane proteins resulting in the assembly of specific plasma membrane domains. The aim is to understand how, through phosphorylation, erzin is able to organise multi-molecular complexes for the structural and functional regulation of plasma membrane domains.

In vivo villin function and gene targeting to the intestine

S. Robine and co-workers are interested in two research approaches:

• Understanding the role of actin-binding proteins in filament organization of the microvilli found at the apical pole of digestive epithelial cells (movie 3).

Movie 3: Accelerated movement of the bacterium S. flexneri within polarized MDCK epithelial cells expressing mCherry-labelled wild villin protein, compared to cells expressing mutant RRI villin protein.

• The second approach aims to develop transgenic mice targeting genes of interest in the digestive epithelium, in a constitutive or inducible manner, thanks to the highly specific villin promoter. This strategy has led to the characterization of signalling pathways important for intestinal homeostasis as well as tumorigenesis, such as the Wnt, Ras, Notch and p53 (Fig. 1).

Fig. 1 

Last update: October 2008

Key publications

2008

• Loubery S, Wilhelm C, Hurbain I, Neveu S, Louvard D, Coudrier E.
  Different microtubule motors move early and late endocytic compartments
  Traffic, Apr;9(4):492-509
• Naba, A., Reverdy, C., Louvard, D., Arpin, M.
  Spatial recruitment and activation of the Fes kinase by ezrin promotes HGF-induced cell scattering
  EMBO J, 27:38-50

2007

• Vignjevic, D., Schoumacher, M., Gavert, N., Janssen, K. P., Jih, G., Lae, M., Louvard, D., Ben-Ze'ev, A., Robine, S.
  Fascin, a Novel Target of {beta}-Catenin-TCF Signaling, Is Expressed at the Invasive Front of Human Colon Cancer
  Cancer Res, 67:6844-6853
• C.Revenu, M.Courtois, A. Michelot, C.Sykes, D. Louvard and
  S.Robine
  Villin severing activity enhances actin-based motility in vivo
  Molecular Biology of the Cell, 18(3):827-38

2005

• S. Fre, M. Huyghe, P. Mourikis, S. Robine, D. Louvard and S. Artavanis-Tsakonas
  Notch signals control the fate of immature progenitor cells in the intestine
  Nature, 435,964-968