Stomach Development Is Dependent on Fibroblast Growth Factor 10/Fibroblast Growth Factor Receptor 2b–Mediated Signaling

doi:10.1053/j.gastro.2006.02.018

Gastroenterology

Volume 130, Issue 4, April 2006, Pages 1233-1244

https://doi.org/10.1053/j.gastro.2006.02.018 Get rights and content

Background & Aims: Fibroblast growth factors (Fgfs) and their receptors (Fgfrs) are important intercellular signaling molecules that are essential to mammalian embryonic development. The signaling pathways between endoderm-derived gastric epithelium and the surrounding mesenchyme are largely unknown; however, the developmental expression profile of the IIIb isoform of Fgfr2 (Fgfr2b) and its main ligand, Fgf10, suggest that they may be strong candidates. Mice lacking either component (Fgfr2b^−/− or Fgf10^−/−) were examined to determine the role of Fgfr2b-mediated signaling during gastric organogenesis. Methods: Stomachs from embryonic day 13.5–18.5 Fgfr2b^−/−, Fgf10^−/−, and wild-type littermates were collected and analyzed by conventional histology, immunohistochemistry, in situ hybridization, and electron microscopy. Results: Fgfr2b^−/− and Fgf10^−/− fetuses had stomachs smaller than wild-type, consisting of relatively proportionate forestomach but disproportionately reduced glandular stomach, the mucosa of which has low cytoarchitectural complexity with a spiral arrangement of large mucosal folds. During mid to late fetal stages (embryonic day 15.5–18.5), epithelial differentiation to mucous and chief cell lineages was rudimentary, with no expression of several early cytodifferentiation markers including GATA4, GATA6, and H⁺/K⁺-adenosine triphosphatase and abnormal expression of members of the hedgehog family of signaling molecules. Conclusions: Fgfr2b and Fgf10 are part of a signaling network with Sonic hedgehog and Indian hedgehog that are essential to anterior-posterior and radial patterning in gastric development.

Section snippets

Generation of Mice

All animal experiments were performed according to UK Home Office regulations. The targeted disruption of Fgfr2b¹⁹ and Fgf10²³ has been described previously. Both Fgfr2b and Fgf10 heterozygotes were intercrossed to generate homozygous null embryos at the required embryonic stage, and yolk sacs were used for genotyping by polymerase chain reaction.¹⁹ The morning of vaginal plug appearance was considered E0.5. Control mice consisted of wild-type (wt) and heterozygous littermates, the latter being

Absence of Fgfr2b or Its Ligand Fgf10 Results in Defective Stomach Growth and Patterning During Development

Stomachs were dissected from wt, Fgfr2b^−/−, and Fgf10^−/− mice between E16.5 and E18.5. Mutant stomachs were small, although roughly in proportion to the reduced size of the mouse as a whole (Figure 1 A). In both cases, the forestomach appeared to show a slight loss of definition of the longitudinal folds but no other gross changes. The muscular wall of the stomach appeared normal. The glandular epithelial lining of the corpus region of both Fgfr2b^−/− and Fgf10^−/− mice appeared devoid of normal

Discussion

We report the gastric developmental defects exhibited by mice null for Fgf10 or its receptor, Fgfr2b, during fetal development. Mutant stomachs from both mutants were reduced in size when compared with those from normal littermates. This finding is consistent with an overall proportionate reduction in size of mutants versus controls and may also be due to a decrease in proliferation observed here at E13.5.19, 23, 24 Histologic analysis showed that the glandular epithelial architecture was

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Basic–alimentary tractStomach Development Is Dependent on Fibroblast Growth Factor 10/Fibroblast Growth Factor Receptor 2b–Mediated Signaling

Section snippets

Generation of Mice

Absence of Fgfr2b or Its Ligand Fgf10 Results in Defective Stomach Growth and Patterning During Development

Discussion

Dev Biol

Gastroenterology

Dev Cell

J Biol Chem

Dev Biol

Biochem Biophys Res Commun

Dev Biol

Dev Biol

Mech Dev

Biochem Biophys Res Commun

Dev Biol

J Biol Chem

Epithelial-mesenchymal interactions in differentiation of stomach epithelium in fetal mice

Anat Embryol

Gastric epithelial morphogenesis in normal and transgenic mice

Am J Physiol

Division of the mouse gastric mucosa into zymogenic and mucous regions on the basis of gland features

Am J Anat

Dynamic histology of the antral epithelium in the mouse stomach: I. Architecture of antral units

Am J Anat

Activin receptor patterning of foregut organogenesis

Genes Dev

Hedgehog signals regulate multiple aspects of gastrointestinal development

Development

Basic–alimentary tract
Stomach Development Is Dependent on Fibroblast Growth Factor 10/Fibroblast Growth Factor Receptor 2b–Mediated Signaling