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 knock out mice combined with cell culture experiments and siRNA mediated knock down and identified a lama5 specific gene expression signature. Our data provide a mechanistic link between laminin alpha5 gene deficiency and the physiological phenotype. We show that laminin alpha5 plays a crucial role in both epithelial and mesenchymal cell behavior by regulating Wnt and PI3K signaling. We provide evidence that a laminin-511 substratum prevents chemical-induced apoptosis in a PI3K-dependent manner and that laminin-511 represses Wnt 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 the PI3K/Akt and Wnt signaling pathways that are interconnected. Thus deregulated adhesion to laminin-511 may be instrumental in diseases such as human pathologies of the gut where laminin-511 is abnormally expressed. The microarray experiments were performed in quadruple with independently prepared RNA from mutant (Laminin alpha5-deficient mouse) and wild-type embryonic intestines derived from 4 different litters. For each RNA sample, a dye-swap labeling and hybridization was performed using a common reference RNA sample corresponding to 15.5-day embryonic intestines of C57B1/6J mice.

ORGANISM(S): Mus musculus

SUBMITTER: Bernard Jost 

PROVIDER: E-GEOD-31334 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress