Multiple roles of epithelial heparan sulfate in stomach morphogenesis

Abstract

Heparan sulfate proteoglycans (HSPGs) have been shown to regulate various developmental processes. However, the function of heparan sulfate (HS) in the development of mammalian stomach has not been characterized yet. Here we investigate the role of epithelial HS in embryonic stomach by examining glycosyltransferase gene Exostoses (multiple) 1 (Ext1)-deficient mice. We show that HS exhibits specific and dynamic expression pattern in mouse embryonic stomach. Depletion of the epithelial HS leads to stomach hypoplasia with phenotypic differences in the gastric mucosa between forestomach and hindstomach. In the posterior stomach, HS depletion disrupts glandular stomach patterning and cytodifferentiation via attenuation of Fgf signaling activity. Inhibition of Fgf signaling in vitro recapitulates the patterning defect. Ligand and carbohydrate engagement assay (LACE) reveals a diminished assembly of Fgf10/Fgfr2b in mutant. In the anterior stomach, loss of epithelial HS leads to stratification and differentiation defects of multilayered squamous epithelium, along with reduced Hh and Bmp signaling activity. Our data demonstrate that epithelial HS plays multiple roles in regulating mammalian stomach morphogenesis in a region-specific manner.