Dataset Information

Abnormal Wnt and PI3Kinase signaling in the malformed intestine of lama5 deficient mice.

ABSTRACT: Laminins are major constituents of basement membranes and are essential for tissue homeostasis. Laminin-511 is highly expressed in the intestine and its absence causes severe malformation of the intestine and embryonic lethality. To understand the mechanistic role of laminin-511 in tissue homeostasis, we used RNA profiling of embryonic intestinal tissue of lama5 knockout mice and identified a lama5 specific gene expression signature. By combining cell culture experiments with mediated knockdown approaches, we provide a mechanistic link between laminin ?5 gene deficiency and the physiological phenotype. We show that laminin ?5 plays a crucial role in both epithelial and mesenchymal cell behavior by inhibiting Wnt and activating PI3K signaling. We conclude that conflicting signals are elicited in the absence of lama5, which alter cell adhesion, migration as well as epithelial and muscle differentiation. Conversely, adhesion to laminin-511 may serve as a potent regulator of known interconnected PI3K/Akt and Wnt signaling pathways. Thus deregulated adhesion to laminin-511 may be instrumental in diseases such as human pathologies of the gut where laminin-511 is abnormally expressed as it is shown here.

SUBMITTER: Ritie L

PROVIDER: S-EPMC3364287 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Abnormal Wnt and PI3Kinase signaling in the malformed intestine of lama5 deficient mice.

Ritié Léa L Spenlé Caroline C Lacroute Joël J Bolcato-Bellemin Anne-Laure AL Lefebvre Olivier O Bole-Feysot Christine C Jost Bernard B Klein Annick A Arnold Christiane C Kedinger Michèle M Bagnard Dominique D Orend Gertraud G Simon-Assmann Patricia P

PloS one 20120530 5

Laminins are major constituents of basement membranes and are essential for tissue homeostasis. Laminin-511 is highly expressed in the intestine and its absence causes severe malformation of the intestine and embryonic lethality. To understand the mechanistic role of laminin-511 in tissue homeostasis, we used RNA profiling of embryonic intestinal tissue of lama5 knockout mice and identified a lama5 specific gene expression signature. By combining cell culture experiments with mediated knockdown ...[more]

PMID: 22666383

Similar Datasets

Project description:Roquin, an E3 ubiquitin ligase that localizes to cytosolic RNA granules, is involved in regulating mRNA stability and translation. Mice that have a M199R mutation in the Roquin protein (referred to as sanroque or Roquin(san/san) mice) develop autoimmune pathologies, although the extent to which these occur in the intestinal mucosa has not been determined. Here, we demonstrate that Roquin(san/san) mice reproducibly develop intestinal inflammation in the small intestine but not the colon. Similarly, mice generated in our laboratory in which the Roquin gene was disrupted by insertion of a gene trap cassette (Roquin(gt/gt) mice) had small intestinal inflammation that mimicked that of Roquin(san/san) mice. MLN cells in Roquin(san/san) mice consisted of activated proliferating T cells, and had increased numbers of CD44(hi) CD62L(lo) KLRG1(+) short-lived effector cells. Proportionally more small intestinal intraepithelial lymphocytes in Roquin(san/san) mice expressed the ICOS T cell activation marker. Of particular interest, small intestinal lamina propria lymphocytes in Roquin(san/san) mice consisted of a high proportion of Gr-1(+) T cells that included IL-17A(+) cells and CD8(+) IFN-?(+) cells. Extensive cytokine dysregulation resulting in both over-expression and under-expression of chemotactic cytokines occurred in the ileum of Roquin(san/san) mice, the region most prone to the development of inflammation. These findings demonstrate that chronic inflammation ensues in the intestine following Roquin alteration either as a consequence of protein mutation or gene disruption, and they have implications for understanding how small intestinal inflammation is perpetuated in Crohn's disease (CD). Due to the paucity of animal models of CD-like pathophysiology in the small intestine, and because the primary gene/protein defects of the Roquin animal systems used here are well-defined, it will be possible to further elucidate the underlying genetic and molecular mechanisms that drive the disease process.

Dataset Information

Abnormal Wnt and PI3Kinase signaling in the malformed intestine of lama5 deficient mice.

Publications

Abnormal Wnt and PI3Kinase signaling in the malformed intestine of lama5 deficient mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets