Nodal and Lefty signaling regulates the growth of pancreatic cells

Abstract

Nodal and its antagonist, Lefty, are important mediators specifying the laterality of the organs during embryogenesis. Nodal signals through activin receptors in the presence of its co‐receptor, Cripto. In the present study, we investigated the possible roles of Nodal and Lefty signaling during islet development and islet regeneration. By using immunohistochemistry, RT‐PCR and Western blotting methods, we found that both Nodal and Lefty are expressed in the pancreas during embryogenesis and islet regeneration. Exposure to recombinant mouse Nodal (rmNodal) inhibited the proliferation of a pancreatic progenitor cell line, AR42J cells, and conversely, recombinant mouse Lefty‐1 (rmLefty‐1) stimulated the proliferation of these cells. We also present evidence that the proliferation of the pancreatic progenitor cell line induced by Lefty‐1 involves phosphorylation of MAPK, activation of Akt and Bcl‐2 upregulation. In vivo blockade of endogenous Lefty using neutralizing a Lefty‐1 monoclonal antibody results in a significantly decreased proliferation of duct epithelial cells suggesting that Lefty‐1 is necessary for epithelial cell expansion during islet regeneration. Together, our data provide evidence for a novel role of Nodal‐Lefty signaling during pancreatic development and islet regeneration.