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Perreault N. Epithelial BMP signaling is required for proper specification of epithelial cell lineages and gastric endocrine cells. Am J Physiol Gastrointest Liver Physiol 300: G1065-G1079, 2011. First published March 17, 2011 doi:10.1152/ajpgi.00176.2010.-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⌬GEC 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 ⌬GEC 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 (Ͻ100 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. bone morphogenetic protein; gastric cell lineages; spasmolytic polypeptide-expressing metaplasia

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AIMS: The phosphatase and tensin homolog (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/ AKT pathway, is one of the most frequently mutated/deleted gene in various human cancers. PTEN has also been shown to regulate numerous cellular processes such as genomic stability, stem cell renewal, senescence and cell differentiation. However, the potential effects of Pten on gastric organogenesis and homeostasis have not yet been explored. The aim of our study is to investigate the role of epithelial Pten signaling in the maintenance and specification of gastric epithelium. METHODS: Using the Cre/loxP system, we have generated a mouse model with a deletion of Pten exclusively in the foregut endoderm (PtenαGEC). Glandular architecture was assessed with H&E staining. Analysis of cell proliferation was performed by immunofluorescence with a PCNA antibody. Gastric cell type patterns from control and mutant mice were analyzed by antibody- specific immunostaining, alcian blue and Periodic Acid Schiff stainings. RESULTS: PtenαGEC mice are viable and have no severe abnormality in gastric organogenesis. Loss of Pten in the stomach epithelium was confirmed by IHC and, as expected, leads to an increase of p-Akt in the mutant gastric glands. Histological analysis by H&E staining demonstrates a disorganized glandular architecture associated with cystic regions in the corpus from 4 months of age. The PtenαGEC mice display a delocalization and upregulation in epithelial proliferation associated to an increase of the glands length. Analysis of the different cell lineages shows an increase in the mucus cell population. Furthermore, chromogranin A immunostaining shows an increase in the number of enteroendocrine cells in Pten mutant mice. Analysis of parietal cells reveals a significant decrease in this cell population in PtenαGEC mice. Surprisingly, zymogenic cells are absent from the glandular epithelium in mutant mice, whereas GSII positive cells, specific for neck cells, are increased and delocalized to the basal region. The latter observations suggest a possible induction of SPEM (spasmolytic polypeptide-expressing metaplasia) in these mice. Furthermore with aging, loss of PTEN leads to an increasing inflammatory process demonstrated by the expression of myeloperoxidase positive cells in the cystic regions and the mesenchyme. CONCLUSION: Altogether, our results indicate that PTEN in the gastric epithelium impacts on gastric gland architecture, negatively regulates the proliferation and plays an important role in the regulation of the cytodifferentiation and maturation of gastric cells. Finally loss epithelial Pten is sufficient for SPEM development and presence of inflammatory markers with age. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2251. doi:1538-7445.AM2012-2251

Background: HNF4α, also referred as maturity onset diabetes of the young (MODY-1), is a transcription factor that regulates differentiation, inflammation and metabolism. HNF4α regulatory function of carbohydrate-lipid metabolism has been mostly studied in relation to liver and pancreatic functions. Since the gut can actively participate in regulating metabolism, we have investigated HNF4α potential regulatory role in this context. Aims: To evaluate the effect of intestinal epithelial conditional deletion of HNF4α on lipid metabolism. Methods: Control and HNF4α mutant mice were fed with a high-fat diet (HFD) composed of 21.3% protein, 23.6% fat and 41.2% carbohydrate. Physiological parameters were measured using metabolic cages. Fatty acids (fecal, tissular and plasmatic) were assayed by gas chromatographic analysis. Circulating hormones were assessed by ELISA. The intestinal transcriptome was analyzed by qPCR and Affymetrix microarrays. Results: HNF4α mutant mice maintained on HFD were resistant to weight gain as opposed to control mice. This observation was correlated with a significant reduction of visceral adiposity and hepatic lipid storage in mutant mice when compared to controls. Food consumption was not significantly altered among both groups. To investigate whether this phenotype was dependent on altered intestinal epithelial lipid absorption, we assessed lipid transport by measuring residual fecal as well as circulating fatty acids. HNF4α mutant mice exposed to HFD displayed similar levels of fatty acids both in the feces and in circulation when compared to controls. To explore how intestinal epithelial cells could interfere on the resistance to obesity phenotype, transcriptome profiles were compared between mutant and control mice. No specific expression change was observed among gene transcripts linked to lipid transport and metabolism. However, the gastric inhibitory peptide (GIP) gene transcript was found to be significantly reduced in mutant mice. ELISA confirmed a drastic 90% reduction of GIP circulating levels in mutant mice. Conclusions: Conditional deletion of HNF4α from the intestinal epithelium led to a resistance to HFD-induced obesity. This phenomenon was not dependent on gut lipid malabsorption. Since GIP expression is functionally linked to adipose tissue and control obesity state, investigation are currently undergoing to explore a relationship between intestinal epithelial HNF4α regulatory action on GIP hormone expression and obesity outcome.