Multimerin1 and not Galectin-8 tempers WNT signaling to promote gastric chief cell differentiation.

Galectins are a family of proteins that bind galactose-containing glycans. One member, galectin-8, preferentially binds galactose that contains a terminal sulfate. Aberrant expression and secretion of sulfated glycosylation epitopes, such as 3'-Sulfo-LeA/C, is a feature of high-risk human foregut metaplasias. In addition, recent work has demonstrated that 3'-Sulfo-LeC is a marker of mature murine zymogenic chief cells of the stomach and that 3'-Sulfo-LeC epitope is secreted via cathartocytosis during the cellular transition to a metaplastic state. Based on those findings, we used Lgals8-/- mice, to determine whether galectin-8 might play a role in chief cell homeostasis. We observed delayed gastric differentiation in the Lgals8-/- mice but discovered that this phenotype was due to unappreciated deletions of Mmrn1 and Snca in the Lgals8-/- line and not Lgals8. Since, we could not find evidence of alpha-synuclein at either the RNA or protein level in the stomach, we attributed this phenotype to the absence MMRN1. Our data suggest that multimerin-1 tempers WNT stimulation of the gastric corpus at an early age, as evidenced by nuclear beta-catenin staining and proliferation throughout the gland in Mmrn1-/-/Snca-/- mice. Because multimerin-1 is synthesized and secreted from endothelial cells and not from the epithelial compartment, these data uncover a role for mesodermal cells in epithelial developmental and maturation of the mouse stomach. As prior studies have suggested galectin-8 and multimerin-1 exert opposite effects on bone physiology as well as parallel functions in coagulation, future studies using pure knockouts are necessary to refine these phenotypes.