RESUMEN
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.
Asunto(s)
Proteínas Morfogenéticas Óseas/metabolismo , Linaje de la Célula , Células Enteroendocrinas/metabolismo , Células Epiteliales/metabolismo , Mucosa Gástrica/metabolismo , Transducción de Señal , Envejecimiento , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/deficiencia , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Diferenciación Celular , Proliferación Celular , Duodeno/embriología , Duodeno/metabolismo , Células Enteroendocrinas/patología , Células Epiteliales/patología , Mucosa Gástrica/embriología , Mucosa Gástrica/patología , Factor Nuclear 3-gamma del Hepatocito/genética , Factor Nuclear 3-gamma del Hepatocito/metabolismo , Hiperplasia , Integrasas/genética , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Morfogénesis , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
C/EBP transcription factors are involved in the regulation of the intestinal epithelial cell response to inflammatory stimuli. GATA transcription factors modulate C/EBP-dependent transcriptional activation in various cell types. We thus determined whether GATA-4 whose expression is restricted to epithelial cells, modulate C/EBP transcriptional activity and C/EBP-dependent acute phase protein expression in intestinal epithelial cells. Interaction between C/EBPdelta and GATA-4 required both C/EBPdelta leucine zipper and basic DNA-binding domains, and the GATA-4 C-terminal region. C/EBP isoforms and GATA-4 synergistically activated the alpha-acid glycoprotein gene while GATA-4 repressed thiostatin and haptoglobin C/EBP-dependent transactivation. In GATA-4 expressing intestinal epithelial cells, GATA-4 led to decreased C/EBPbeta and C/EBPdelta protein levels, and decreased thiostatin expression in response to IL-1beta and dexamethasone. This correlated with decreased C/EBPdelta recruitment to the thiostatin promoter, as assessed by chromatin immunoprecipitation assays. In contrast, increased AGP expression in response to dexamethasone correlated with increased basal histone H4 acetylation. Thus, GATA-4 may be involved in the establishment of specific intestinal epithelial cell C/EBP-dependent and C/EBP-independent transcriptional responses.