title: Epithelial BMP signaling is required for proper specification of epithelial cell lineages and gastric endocrine cells.
abstract: Bone morphogenetic protein (BMP) signaling within the gastrointestinal tract is complex. BMP ligands and their receptors are expressed in both epithelial and mesenchymal compartments, suggesting bidirectional signaling between these two entities. Despite an increasing interest in BMP signaling in gut physiology and pathologies, the distinct contribution of BMP signaling in the epithelium vs. the mesenchyme in gastrointestinal homeostasis remains to be established. We aimed to investigate the role of epithelial BMP signaling in gastric organogenesis, gland morphogenesis, and maintenance of epithelial cell functions. Using the Cre/loxP system, we generated a mouse model with an early deletion during development of BMP receptor 1A (Bmpr1a) exclusively in the foregut endoderm. Bmpr1a(ΔGEC) mice showed no severe abnormalities in gastric organogenesis, gland epithelial proliferation, or morphogenesis, suggesting only a minor role for epithelial BMP signaling in these processes. However, early loss of BMP signaling in foregut endoderm did impact on gastric patterning, leading to an anteriorization of the stomach. In addition, numbers of parietal cells were reduced in Bmpr1a(ΔGEC) mice. Epithelial BMP deletion significantly increased the numbers of chromogranin A-, ghrelin-, somatostatin-, gastrin-, and serotonin-expressing gastric endocrine cells. Cancer never developed in young adult (<100 days) Bmpr1a-inactivated mice although a marker of spasmolytic polypeptide-expressing metaplasia was upregulated. Using this model, we have uncovered that BMP signaling negatively regulates the proliferation and commitment of endocrine precursor cells. Our data also indicate that loss of BMP signaling in epithelial gastric cells alone is not sufficient to induce gastric neoplasia.
authors.affiliation: Département d’Anatomie et Biologie Cellulaire, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Québec, Canada.
authors.forename: Faïza
authors.initials: F
authors.lastname: Maloum
authors.forename: Joannie M
authors.initials: JM
authors.lastname: Allaire
authors.forename: Jessica
authors.initials: J
authors.lastname: Gagné-Sansfaçon
authors.forename: Evelyne
authors.initials: E
authors.lastname: Roy
authors.forename: Karine
authors.initials: K
authors.lastname: Belleville
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.forename: Jean
authors.initials: J
authors.lastname: Morisset
authors.forename: Julie C
authors.initials: JC
authors.lastname: Carrier
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.forename: Nathalie
authors.initials: N
authors.lastname: Perreault
mesh_terms: D000375:Aging; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000172:deficiency / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D004386:Duodenum / Q000196:embryology / Q000378:metabolism; D019858:Enteroendocrine Cells / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005753:Gastric Mucosa / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000235:genetics / Q000378:metabolism; D006965:Hyperplasia; D019426:Integrases / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D019485:Bone Morphogenetic Proteins; C496506:Foxa3 protein, mouse; D051543:Hepatocyte Nuclear Factor 3-gamma; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; C045073:Cre recombinase; D019426:Integrases