The Syndrome of Arthrogryposis and Palatoschisis (SAP) in Charolais cattle; Abnormal motor innervation and defect in the focalization of 16 S acetylcholinesterase in the end-plates rich regions of the muscle

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The Cellular Prion Protein PrPc Is Involved in the Proliferation of Epithelial Cells and in the Distribution of Junction-Associated Proteins

BACKGROUND: The physiological function of the ubiquitous cellular prion protein, PrP(c), is still under debate. It was essentially studied in nervous system, but poorly investigated in epithelial cells. We previously reported that PrP(c) is targeted to cell-cell junctions of polarized epithelial cells, where it interacts with c-Src. METHODOLOGY/FINDINGS: We show here that, in cultured human enterocytes and in intestine in vivo, the mature PrP(c) is differentially targeted either to the nucleus in dividing cells or to cell-cell contacts in polarized/differentiated cells. By proteomic analysis, we demonstrate that the junctional PrP(c) interacts with cytoskeleton-associated proteins, such as gamma- and beta-actin, alpha-spectrin, annexin A2, and with the desmosome-associated proteins desmoglein, plakoglobin and desmoplakin. In addition, co-immunoprecipitation experiments revealed complexes associating PrP(c), desmoglein and c-Src in raft domains. Through siRNA strategy, we show that PrP(c) is necessary to complete the process of epithelial cell proliferation and for the sub-cellular distribution of proteins involved in cell architecture and junctions. Moreover, analysis of the architecture of the intestinal epithelium of PrP(c) knock-out mice revealed a net decrease in the size of desmosomal junctions and, without change in the amount of BrdU incorporation, a shortening of the length of intestinal villi. CONCLUSIONS/SIGNIFICANCE: From these results, PrP(c) could be considered as a new partner involved in the balance between proliferation and polarization/differentiation in epithelial cells

Les cadhérines : des protéines de structure et de signalisation des jonctions cellule-cellule

Les cadhérines constituent une famille multigénique, d’environ 80 membres, qui comprend les cadhérines classiques, les desmogléines, les desmocollines, les protocadhérines, CNRs, Fats, la sevenpass transmembrane cadherine, la Ret tyrosine kinase. Les domaines répétés EC extracellulaires (domaine N-terminal) sont communs aux membres de la famille et permettent l’adhérence cellulaire par des interactions homophiliques dépendantes du calcium. Les cadhérines sont exprimées depuis l’amibe jusqu’aux mammifères. La complexité biologique représentée par les cadhérines s’exprime à différents niveaux, par la multigénicité de la famille, par les multiples fonctions dans des tissus très différents. Cela nécessite des approches méthodologiques diverses. Chacune des présentations orales de cette session aborde un aspect prometteur, que ce soit dans le domaine de la compréhension fondamentale de l’adhérence cellulaire (R.M. Mège) allant jusqu’à l’échelle de la molécule (H. Feracci), de l’homéostasie physiologique de l’intestin (S.Thenet), du lignage cellulaire (V. Delmas) ou de la transformation cancéreuse (L. Larue)

Extensive multiple innervation and abnormal synaptogenesis in muscular dysgenesis (mdg/mdg) in the mouse embryo

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Le contrôle de la balance survie/apoptose par la E-cadhérine : implication dans l’anoïkis des entérocytes

Les cadhérines sont des glycoprotéines transmembranaires impliquées dans l'adhésion cellule-cellule. Des données récentes de la littérature suggèrent que les cadhérines classiques se comportent comme des récepteurs activés par l’adhérence cellule-cellule et contrôlent des signaux intracellulaires. Dans cet article, nous résumons les travaux concernant le rôle des cadhérines classiques dans le contrôle de la survie cellulaire, et les voies de signalisation impliquées. Nous nous focalisons sur le devenir et le rôle de la E-cadhérine, la principale cadhérine classique exprimée dans les cellule épithéliales, dans l’apoptose induite par le détachement des entérocytes de la matrice extracellulaire (anoïkis). L’ensemble de ces résultats ouvrent de nouvelles perspectives concernant le rôle de la E-cadhérine, une protéine dérégulée dans la majorité des carcinomes et considérée comme un suppresseur de tumeur

Early Loss of E-cadherin from Cell-Cell Contacts Is Involved in the Onset of Anoikis in Enterocytes

International audienceAnoikis, i.e. apoptosis induced by detachment from the extracellular matrix, is thought to be involved in the shedding of enterocytes at the tip of intestinal villi. Mechanisms controlling enterocyte survival are poorly understood. We investigated the role of E-cadherin, a key protein of cell-cell adhesion, in the control of anoikis of normal intestinal epithelial cells, by detaching murine villus epithelial cells from the underlying basement membrane while preserving cell-cell interactions. We show that upon the loss of anchorage, normal enterocytes execute a program of apoptosis within minutes, via a Bcl-2-regulated and caspase-9-dependent pathway. E-cadherin is lost early from cell-cell contacts. This process precedes the execution phase of detachment-induced apoptosis as it is only weakly modulated by Bcl-2 overexpression or caspase inhibition. E-cadherin loss, however, is efficiently prevented by lysosome and proteasome inhibitors. We also found that a blocking anti-E-cadherin antibody increases the rate of anoikis, whereas the activation of E-cadherin using Ecadherin-Fc chimera proteins reduces anoikis. In conclusion, our results stress the striking sensitivity of normal enterocytes to the loss of anchorage and the contribution of E-cadherin to the control of their survival/apoptosis balance. They open new perspectives on the key role of this protein, which is dysregulated in the intestinal epithelium in both inflammatory bowel disease and cancer