FGF10 signaling controls stomach morphogenesis

Abstract

Maintenance of progenitor cell properties in development is required for proper organogenesis of most organs, including those derived from the endoderm. FGF10 has been shown to play a role in both lung and pancreatic development. Here we find that FGF10 signaling controls stomach progenitor maintenance, morphogenesis and cellular differentiation. Through a characterization of the initiation of terminal differentiation of the three major gastric regions in the mouse, forestomach, corpus and antrum, we first describe the existence of a "secondary transition" event occurring in mouse stomach between E15.5 and E16.5. This includes the formation of terminally differentiated squamous cells, parietal, chief and gastric endocrine cells from a pre-patterned gastric progenitor epithelium. Expression analysis of both FGF and Notch signaling components suggested a role of these networks in such progenitors, which was tested through ectopically expressing FGF10 in the developing posterior stomach. These data provide evidence that gastric gland specification and progenitor cell maintenance is controlled by FGF10. The glandular proliferative niche was disrupted in pPDX-FGF10(FLAG) mice leading to aberrant gland formation, and endocrine and parietal cell differentiation was attenuated. These effects were paralleled by changes in Hes1, Shh and Wnt6 expression, suggesting that FGF10 acts in concert with multiple morphogenetic signaling systems during gastric development.

Stomach development, stem cells and disease

“…Another action of BMP signaling in the chick GZ mesenchyme is to activate Sox9, which, in turn, induces SOX9-dependent pyloric features in the overlying epithelium (Smith et al, 2000;Theodosiou and Tabin, 2005). In other tissue interactions, Fgf10 and its receptor Fgfr2 show reciprocal expression in the mouse mesenchyme and epithelium, respectively and the corresponding mutants display significant defects in growth of the glandular stomach, with especially reduced epithelial cell proliferation (Spencer-Dene et al, 2006); conversely, FGF10 hyperactivity expands the epithelium (Nyeng et al, 2007). Thus, stomach patterning and growth are mediated by tissue-specific ligand-receptor interactions in signaling pathways that are widely active, emphasizing the need to understand how these signals elicit distinct outcomes in diverse tissues.…”

Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm

“…Numerous studies have shown that transcription factors in the endoderm of the gastrointestinal tract are regulated by mesenchymal signals, including FGFs. More specifically, FGFs upregulate Nkx2.1 in the early anterior foregut endoderm (Serls et al, 2005), whereas overexpression of Fgf10 in the stomach downregulates Sox2 (Nyeng et al, 2007). In the chick embryo, chick Sox2 levels decrease in distal lung primordia undergoing budding morphogenesis in response to the distal mesenchyme ) that specifically expresses Fgf10 (Cardoso and Lu, 2006).…”

EGFR and Notch signaling respectively regulate proliferative activity and multiple cell lineage differentiation of Drosophila gastric stem cells

“…One major target of Notch signaling in directing cell differentiation in midgut ISCs is the genes of the enhancer of split complex [39], and it is possible that a similar mechanism could be involved in CC/IS cell differentiation. In mammals, Notch signaling components are expressed in the gastric epithelium [40,41], and genetic studies have suggested a requirement of Notch signaling in GSSC maintenance [42]. Notch signaling is also a major determinant in fate choice between luminal and glandular cells in chicken stomach [43].…”