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

作者：Ritie Lea^*; Spenle Caroline; Lacroute Joel; Bolcato Bellemin Anne Laure; Lefebvre Olivier; Bole Feysot Christine; Jost Bernard; Klein Annick; Arnold Christiane; Kedinger Michele; Bagnard Dominique; Orend Gertraud; Simon Assmann Patricia

来源：PLos One, 2012, 7(5): e37710.

DOI：10.1371/journal.pone.0037710

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 alpha 5 gene deficiency and the physiological phenotype. We show that laminin alpha 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.

• 出版日期2012-5-30