Abnormal Wnt and PI3Kinase Signaling in the Malformed Intestine of lama5 Deficient Mice

Laminin-511 is highly expressed in the intestine. To understand the mechanistic role of laminin-511 in tissue homeostasis, the researchers used RNA profiling of embryonic intestinal tissue of lama5 knockout mice and identified a lama5 specific gene expression signature. They show that laminin a5 plays a crucial role in both epithelial and mesenchymal (smooth muscle) 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. The LMa5 deficient intestine also displays a smooth muscle defect and myogenic differentiation markers are affected. Laminin-511 supports adhesion of epithelial cells and Akt phosphorylation. Laminin-511 stimulates the spreading of epithelial and muscle cells (compared to laminin-111). Inhibition of Akt with wortmannin abolished spreading of epithelial cells on laminin-511 as evidenced by cell laminin-511 specifically activates Akt through the PI3K pathway in intestinal epithelial but not in mesenchymal cells. Cell migration was also higher on Laminin-511. Laminin-511 also protects cells against H2O2-induced apoptosis.