A framework for unobstructedness of Galois deformation rings

Sei F ein Zahlkörper, S eine endliche Menge von Stellen von F und Gal F,S die Galoisgruppe der maximalen, auÿerhalb von S unverzweigten Erweiterung von F. Sei k ein endlicher Körper. Die De- formationstheorie von Galoisdarstellungen wurde in den 1980er Jahren von Mazur entwickelt um die Lifts einer gegebenen residuellen Galoisdarstellung ρ : Gal_F,S → GL_n(k) zu untersuchen. Mazur stellte die Frage unter welchen Bedingungen der Funktor, der die Deformationen von ρ zu voll- ständigen Noetherschen W(k)-Algebren beschreibt, unobstruiert ist, d.h. wann H^2 (Gal_F,S , ad ρ) = 0 gilt. Diese Unobstruiertheit impliziert die formale Glattheit des zugehörigen universellen Deforma- tionsringes. In der vorliegenden Arbeit wird eine Methode vorgestellt um Unobstruiertheit aus einer Liste von Standardvermutungen abzuleiten, unter anderem von einem entsprechenden R=T-Satz. Diese Methode wird allgemeiner für eine glatte algebraische Gruppe G über W(k) anstelle von GL_n als Wertebereich von ρ entwickelt. Mithilfe der Methode zeigen wir, dass fast alle Einträge in dem kompatiblen System von Galoisdarstellung zu einer Hilbertschen Modulform einen unobstruierten Deformationsfunktor besitzen und erhalten damit ein Resultat von Gamzon. Des Weit- eren wenden wir die Methode auf eine RACSDC automorphe Darstellung von GL_n(A_F) an und erhalten, unter Ausnutzung von Standardvermutungen, dass eine Teilmenge von Dirichlet-Dichte 1 der Einträge der assoziierten G_n -wertigen Familie von Galoisdarstellungen einen unobstruierten Deformationsfunktor besitzt, wobei G_n das Gruppenschema von Clozel, Harris und Taylor bezeichnet

Sexual dimorphism in PAR2-dependent regulation of primitive colonic cells

International audienceBackground: Sexual dimorphism in biological responses is a critical knowledge for therapeutic proposals. However, gender differences in intestinal stem cell physiology have been poorly studied. Given the important role of the protease-activated receptor PAR2 in the control of colon epithelial primitive cells and cell cycle genes, we have performed a sex-based comparison of its expression and of the effects of PAR2 activation or knockout on cell proliferation and survival functions.Methods: Epithelial primitive cells isolated from colons from male and female mice were cultured as colonoids, and their number and size were measured. PAR2 activation was triggered by the addition of SLIGRL agonist peptide in the culture medium. PAR2-deficient mice were used to study the impact of PAR2 expression on colon epithelial cell culture and gene expression.Results: Colonoids from female mice were more abundant and larger compared to males, and these differences were further increased after PAR2 activation by specific PAR2 agonist peptide. The proliferation of male epithelial cells was lower compared to females but was specifically increased in PAR2 knockout male cells. PAR2 expression was higher in male colon cells compared to females and controlled the gene expression and activation of key negative signals of the primitive cell proliferation. This PAR2-dependent brake on the proliferation of male colon primitive cells was correlated with stress resistance.Conclusions: Altogether, these data demonstrate that there is a sexual dimorphism in the PAR2-dependent regulation of primitive cells of the colon crypt

Sexual dimorphism in PAR(2)-dependent regulation of primitive colonic cells

BACKGROUND: Sexual dimorphism in biological responses is a critical knowledge for therapeutic proposals. However, gender differences in intestinal stem cell physiology have been poorly studied. Given the important role of the protease-activated receptor PAR2 in the control of colon epithelial primitive cells and cell cycle genes, we have performed a sex-based comparison of its expression and of the effects of PAR2 activation or knockout on cell proliferation and survival functions. METHODS: Epithelial primitive cells isolated from colons from male and female mice were cultured as colonoids, and their number and size were measured. PAR2 activation was triggered by the addition of SLIGRL agonist peptide in the culture medium. PAR2-deficient mice were used to study the impact of PAR2 expression on colon epithelial cell culture and gene expression. RESULTS: Colonoids from female mice were more abundant and larger compared to males, and these differences were further increased after PAR2 activation by specific PAR2 agonist peptide. The proliferation of male epithelial cells was lower compared to females but was specifically increased in PAR2 knockout male cells. PAR2 expression was higher in male colon cells compared to females and controlled the gene expression and activation of key negative signals of the primitive cell proliferation. This PAR2-dependent brake on the proliferation of male colon primitive cells was correlated with stress resistance. CONCLUSIONS: Altogether, these data demonstrate that there is a sexual dimorphism in the PAR2-dependent regulation of primitive cells of the colon crypt.status: publishe

CKIP-1 regulates mammalian and zebrafish myoblast fusion

Multinucleated muscle fibres arise by fusion of precursor cells called myoblasts. We previously showed that CKIP-1 ectopic expression in C2C12 myoblasts increased cell fusion. In this work, we report that CKIP-1 depletion drastically impairs C2C12 myoblast fusion in vitro and in vivo during zebrafish muscle development. Within developing fast-twich myotome, Ckip-1 localises at the periphery of fast precursor cells, closed to the plasma membrane. Unlike wild-type myoblasts that form spatially arrayed multinucleated fast myofibres, Ckip-1-deficient myoblasts show a drastic reduction in fusion capacity. A search for CKIP-1 binding partners identified the ARPC1 subunit of Arp2/3 actin nucleation complex essential for myoblast fusion. We demonstrate that CKIP-1, through binding to plasma membrane phosphoinositides via its PH domain, regulates cell morphology and lamellipodia formation by recruiting the Arp2/3 complex at the plasma membrane. These results establish CKIP-1 as a regulator of cortical actin that recruits the Arp2/3 complex at the plasma membrane essential for muscle precursor elongation and fusion

Active thrombin produced by the intestinal epithelium controls mucosal biofilms

International audienceProteolytic homeostasis is important at mucosal surfaces, but its actors and their precise role in physiology are poorly understood. Here we report that healthy human and mouse colon epithelia are a major source of active thrombin. We show that mucosal thrombin is directly regulated by the presence of commensal microbiota. Specific inhibition of luminal thrombin activity causes macroscopic and microscopic damage as well as transcriptomic alterations of genes involved in host-microbiota interactions. Further, luminal thrombin inhibition impairs the spatial segregation of microbiota biofilms, allowing bacteria to invade the mucus layer and to translocate across the epithelium. Thrombin cleaves the biofilm matrix of reconstituted mucosa-associated human microbiota. Our results indicate that thrombin constrains biofilms at the intestinal mucosa. Further work is needed to test whether thrombin plays similar roles in other mucosal surfaces, given that lung, bladder and skin epithelia also express thrombin

Increased mucosal thrombin is associated with Crohn's disease and causes inflammatory damage through Protease-Activated Receptors activation

International audienceBackground and Aims: Thrombin levels in the colon of Crohn’s disease patients have recently been found to be elevated 100-fold compared to healthy controls. Our aim was to determine whether and how dysregulated thrombin activity could contribute to local tissue malfunctions associated with Crohn’s disease.Methods: Thrombin activity was studied in tissues from Crohn’s disease patients and healthy controls. Intracolonic administration of thrombin to wild-type or protease-activated receptor-deficient mice was used to assess the effects and mechanisms of local thrombin upregulation. Colitis was induced in rats and mice by the intracolonic administration of trinitrobenzene sulfonic acid. Results: Active forms of thrombin were increased in Crohn's disease patient tissues. Elevated thrombin expression and activity were associated with intestinal epithelial cells. Increased thrombin activity and expression were also a feature of experimental colitis in rats. Colonic exposure to doses of active thrombin comparable to what is found in inflammatory bowel disease tissues caused mucosal damage and tissue dysfunctions in mice, through a mechanism involving both Protease-Activated Receptors-1 and -4. Intracolonic administration of the thrombin inhibitor Dabigatran, as well as inhibition of protease-activated receptor-1, prevented trinitrobenzene sulfonic acid-induced colitis in rodent models.Conclusions: Our data demonstrated that increased local thrombin activity, as it occurs in the colon of patients with inflammatory bowel disease, causes mucosal damage and inflammation. Colonic thrombin and protease-activated receptor-1 appear as possible mechanisms involved in mucosal damage and loss of function and therefore represent potential therapeutic targets for treating inflammatory bowel disease