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Stomach Organ and Cell Lineage Differentiation: From Embryogenesis to Adult Homeostasis

2016; Elsevier BV; Volume: 2; Issue: 5 Linguagem: Inglês

10.1016/j.jcmgh.2016.05.006

2352-345X

Spencer G. Willet, Jason C. Mills,

Congenital heart defects research

Gastric diseases cause considerable worldwide burden. However, the stomach is still poorly understood in terms of the molecular–cellular processes that govern its development and homeostasis. In particular, the complex relationship between the differentiated cell types located within the stomach and the stem and progenitor cells that give rise to them is significantly understudied relative to other organs. In this review, we highlight the current state of the literature relating to specification of gastric cell lineages from embryogenesis to adulthood. Special emphasis is placed on substantial gaps in knowledge about stomach specification that we think should be tackled to advance the field. For example, it has long been assumed that adult gastric units have a granule-free stem cell that gives rise to all differentiated lineages. Here, we point out that there are also other models that fit all extant data, such as long-lived, lineage-committed progenitors that might serve as a source of new cells during homeostasis. Gastric diseases cause considerable worldwide burden. However, the stomach is still poorly understood in terms of the molecular–cellular processes that govern its development and homeostasis. In particular, the complex relationship between the differentiated cell types located within the stomach and the stem and progenitor cells that give rise to them is significantly understudied relative to other organs. In this review, we highlight the current state of the literature relating to specification of gastric cell lineages from embryogenesis to adulthood. Special emphasis is placed on substantial gaps in knowledge about stomach specification that we think should be tackled to advance the field. For example, it has long been assumed that adult gastric units have a granule-free stem cell that gives rise to all differentiated lineages. Here, we point out that there are also other models that fit all extant data, such as long-lived, lineage-committed progenitors that might serve as a source of new cells during homeostasis. SummaryThis review details the current understanding of gastric specification during development and adult homeostasis. This review details the current understanding of gastric specification during development and adult homeostasis. The adult stomach produces acid and enzymes that aid in food digestion and kill microbes, and it regulates delivery of food to the small intestine. The stomach also works remotely via its endocrine cells, which send distal signals to help coordinate hunger/satiety and Ca++ homeostasis.1Hunt R.H. Camilleri M. Crowe S.E. et al.The stomach in health and disease.Gut. 2015; 64: 1650-1668Crossref PubMed Scopus (0) Google Scholar The stomach comprises tissues originating from all 3 embryonic germ layers including the ectodermally derived enteric nerves, mesodermally derived smooth muscle and mesenchymal cells, and the endodermally derived epithelium lining the lumen of the stomach. In this review, we largely focus on the processes governing epithelial development and homeostasis. The glandular epithelium in most mammals is arranged into 2 principal compartments: corpus and antrum (Figure 1). Both compartments are composed of a single layer of epithelial cells arranged into invaginated units. The principal cellular constituents of corpus units include the surface mucous (pit/foveolar) cells, acid-secreting parietal cells, mucous neck cells, digestive-enzyme secreting (zymogenic) chief cells, endocrine cells, and isthmal cells with undifferentiated features that likely serve as multipotent stem cells. The antral units can contain some chief and parietal cells depending on the species, but primarily are composed of pit/foveolar cells on the surface and deep glandular cells that express markers of both mucous neck cells and chief cells (Figure 1). Scattered throughout the corpus and antrum are the rarer endocrine cells, each type named for the predominant hormone they secrete (eg, gastrin-secreting G cells of the antrum). Understanding cellular development in the normal stomach should help us better understand the origins of gastric cancer, one of the most common causes of cancer death worldwide.2Stewart B.W. Wild C. International Agency for Research on Cancer et al.World cancer report 2014. International Agency for Research on Cancer WHO Press, Lyon2014Google Scholar Most gastric cancer is initiated in the setting of chronic infection with the bacterium Helicobacter pylori, which is estimated to infect more than half the world's population.3Hatakeyama M. Helicobacter pylori CagA and gastric cancer: a paradigm for hit-and-run carcinogenesis.Cell Host Microbe. 2014; 15: 306-316Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In addition to increasing the risk for gastric cancer, it is also the cause of most ulcers of the stomach and duodenum. Those patients at risk for gastric cancer show a response to infection with H pylori characterized by an overall loss of specific differentiated cell lineages, a condition known pathologically as chronic atrophic gastritis. Molecular and cellular mechanistic studies have shown that chronic atrophic gastritis is not characterized simply by a chronic inflammatory infiltrate (gastritis) and the loss of acid-secreting parietal cells (oxyntic atrophy), but also by changes in differentiation of the chief cells (metaplasia).4Lennerz J.K. Kim S.H. Oates E.L. et al.The transcription factor MIST1 is a novel human gastric chief cell marker whose expression is lost in metaplasia, dysplasia, and carcinoma.Am J Pathol. 2010; 177: 1514-1533Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 5Schmidt P.H. Lee J.R. Joshi V. et al.Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma.Lab Invest. 1999; 79: 639-646PubMed Google Scholar, 6Nam K.T. Lee H.J. Sousa J.F. et al.Mature chief cells are cryptic progenitors for metaplasia in the stomach.Gastroenterology. 2010; 139: 2028-2037 e9Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar A thorough understanding of the processes that control the specification of cells within the gastric epithelium during development and adult homeostasis could be crucial to deciphering the disease etiology, particularly the metaplastic changes that arise after H pylori infection. However, currently in the stomach, in both the adult and embryonic state, there is a rudimentary understanding of the cell lineage relationships. Furthermore, there is also a marked lack of lineage-specific markers and genetic tools for studying development and differentiation. In this review, we highlight the relatively limited information we have about stomach specification, starting with the embryo and continuing through adulthood. One caveat is that most of the work on mammalian gastric development has been in rodents. Much work also has been performed in nonmammalian model organisms such as in chicks. The degree to which human gastric development follows the same rules as rodents—let alone nonmammalian vertebrates—is not known in most cases. Because of our relatively close ancestry, it is likely that most developmental patterns will be similar between human beings and these model organisms. However, there are some known differences. For example, the human stomach is lined entirely by glandular units while the rodent stomach contains an additional anatomic compartment known as the forestomach, which is not glandular at all, but rather is lined with squamous epithelium (Figure 1). In the human stomach, up to half of antral units harbor parietal cells, whereas they are absent from antral units in the rodent.7Choi E. Roland J.T. Barlow B.J. et al.Cell lineage distribution atlas of the human stomach reveals heterogeneous gland populations in the gastric antrum.Gut. 2014; 63: 1711-1720Crossref PubMed Scopus (0) Google Scholar In addition, chief cells in the rodent express gastric intrinsic factor, whereas intrinsic factor is expressed by parietal cells in human beings.8Levine J.S. Nakane P.K. Allen R.H. Immunocytochemical localization of human intrinsic factor: the nonstimulated stomach.Gastroenterology. 1980; 79: 493-502Abstract Full Text PDF PubMed Google Scholar Gastric specification in the mouse begins during gastrulation with derivation of the endodermal germ layer that eventually will seed the epithelial lining of the digestive, respiratory, and urogenital systems. The endoderm germ layer is formed by the ingression of epiblast cells through the primitive streak. As the cells exit the primitive streak, they arrange into a single-layered epithelial sheet on the outside of the embryo (embryonic day [E]6–E7.5). This sheet forms pockets at the anterior (future foregut) and posterior (future hindgut) end of the embryo and progressively zippers into a complete gut tube. Zippering of the gut tube, mesodermal growth, and embryonic turning transform the endodermal sheet on the outside of the embryo into an internal tube consisting of 3 major regions: foregut, midgut, and hindgut (E7.5–E9).9Zorn A.M. Wells J.M. Vertebrate endoderm development and organ formation.Annu Rev Cell Dev Biol. 2009; 25: 221-251Crossref PubMed Scopus (216) Google Scholar Regional and subsequent organ identity is assembled within the naive, as yet unspecified, gut tube through the integration of signaling inputs from mesodermal tissues located apposed to the endoderm and the endodermal progenitors themselves.10McLin V.A. Henning S.J. Jamrich M. The role of the visceral mesoderm in the development of the gastrointestinal tract.Gastroenterology. 2009; 136: 2074-2091Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar One recognizable output of the stage when regional identity is acquired is a pattern of expression of overlapping transcription factor domains that facilitate subsequent organ-specific differentiation programs. Stomach epithelial progenitors derive from the foregut region of the endoderm, which also gives rise to liver, pancreas, lungs, and the luminal gastrointestinal organs from the pharynx to the anterior duodenum. Signaling pathways and transcription factors that drive specification of pregastric endodermal progenitors from other emerging organs within the foregut have not been well characterized.11Khurana S. Mills J.C. The gastric mucosa development and differentiation.Prog Mol Biol Transl Sci. 2010; 96: 93-115Crossref PubMed Scopus (0) Google Scholar However, a number of signaling pathways that promote or restrict foregut identity by patterning the anterior/posterior axis of the endoderm are known. Retinoic acid (RA), for example, has a complex spatiotemporal role patterning the anterior–posterior axis of the endoderm. During late gastrulation, RA signaling promotes the specification of posterior endodermal fates over anterior endodermal fates, particularly at the foregut–midgut boundary.12Stafford D. Prince V.E. Retinoic acid signaling is required for a critical early step in zebrafish pancreatic development.Curr Biol. 2002; 12: 1215-1220Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 13Bayha E. Jorgensen M.C. Serup P. et al.Retinoic acid signaling organizes endodermal organ specification along the entire antero-posterior axis.PLoS One. 2009; 4: e5845Crossref PubMed Scopus (0) Google Scholar Subsequently, RA signaling is required to promote the development of a number of foregut tissues. Animals with defective RA signaling have abnormal stomach development, but a specific consequence to gastric specification is unclear.14Wang Z. Dolle P. Cardoso W.V. et al.Retinoic acid regulates morphogenesis and patterning of posterior foregut derivatives.Dev Biol. 2006; 297: 433-445Crossref PubMed Scopus (0) Google Scholar WNT and fibroblast growth factor (FGF) signals produced by the mesoderm promote expression of posterior endodermal markers such as Cdx2 over anterior endodermal markers.15Wells J.M. Melton D.A. Early mouse endoderm is patterned by soluble factors from adjacent germ layers.Development. 2000; 127: 1563-1572PubMed Google Scholar, 16Dessimoz J. Opoka R. Kordich J.J. et al.FGF signaling is necessary for establishing gut tube domains along the anterior-posterior axis in vivo.Mech Dev. 2006; 123: 42-55Crossref PubMed Scopus (0) Google Scholar, 17Sherwood R.I. Maehr R. Mazzoni E.O. et al.Wnt signaling specifies and patterns intestinal endoderm.Mech Dev. 2011; 128: 387-400Crossref PubMed Scopus (0) Google Scholar Studies in zebrafish also have shown that bone morphogenetic protein (BMP) signaling drives posterior over anterior endodermal fates.18Tiso N. Filippi A. Pauls S. et al.BMP signalling regulates anteroposterior endoderm patterning in zebrafish.Mech Dev. 2002; 118: 29-37Crossref PubMed Scopus (0) Google Scholar Through the study of other endodermal organs, a number of tissues have been shown to produce important signaling molecules to promote foregut organ specification. For example, the dorsal aorta and notochord produce several key signaling molecules involved in dorsal pancreatic specification.19Hebrok M. Kim S.K. Melton D.A. Notochord repression of endodermal Sonic hedgehog permits pancreas development.Genes Dev. 1998; 12: 1705-1713Crossref PubMed Google Scholar, 20Kim S.K. Hebrok M. Melton D.A. Notochord to endoderm signaling is required for pancreas development.Development. 1997; 124: 4243-4252PubMed Google Scholar These same tissues also could impact pregastric gene expression given the proximity of gastric and dorsal pancreatic progenitors. Ventral tissues, including cardiac mesoderm, also could impact gastric specification from other ventral organs such as the liver and lung.21Bort R. Martinez-Barbera J.P. Beddington R.S. et al.Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas.Development. 2004; 131: 797-806Crossref PubMed Scopus (0) Google Scholar Other signaling pathways such as sonic hedgehog (Shh) have been implicated in gastric growth through epithelial to mesenchyme signaling, although Shh does not appear to be involved in gastric specification.22Mao J. Kim B.M. Rajurkar M. et al.Hedgehog signaling controls mesenchymal growth in the developing mammalian digestive tract.Development. 2010; 137: 1721-1729Crossref PubMed Scopus (62) Google Scholar During endodermal specification, a highly conserved core transcription network (including FoxA, Gata, Sox17, and Mixl1 transcription factors) is activated and guides the growth and survival of endodermal cells before regionalization.23Grapin-Botton A. Constam D. Evolution of the mechanisms and molecular control of endoderm formation.Mech Dev. 2007; 124: 253-278Crossref PubMed Scopus (0) Google Scholar Expression of these transcription factors in early endoderm is necessary to generate foregut progenitors that give rise to the stomach. As the endoderm regionalizes, a number of transcription factors are expressed either throughout the foregut endoderm or regionally in the pregastric domain. Broadly expressed transcription factors such as Foxa1/2/3, Gata4/6, Hnf1β, and Sox2 all could play an important role in gastric specification (Figure 2). For example, the FoxA family is expressed throughout the early endoderm and is important in the development of a number of organs including the liver, pancreas, and intestine.24Lee C.S. Friedman J.R. Fulmer J.T. et al.The initiation of liver development is dependent on Foxa transcription factors.Nature. 2005; 435: 944-947Crossref PubMed Scopus (276) Google Scholar, 25Gao N. LeLay J. Vatamaniuk M.Z. et al.Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development.Genes Dev. 2008; 22: 3435-3448Crossref PubMed Scopus (0) Google Scholar, 26Ye D.Z. Kaestner K.H. Foxa1 and Foxa2 control the differentiation of goblet and enteroendocrine L- and D-cells in mice.Gastroenterology. 2009; 137: 2052-2062Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The specific role of this family in the stomach has yet to be determined, however, FoxAs are known to be involved in promoting Pdx1 expression in the foregut (Figure 2). Because Pdx1 is expressed only in the gastric antrum and not the more proximal corpus,27Offield M.F. Jetton T.L. Labosky P.A. et al.PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum.Development. 1996; 122: 983-995Crossref PubMed Google Scholar FoxA factors thus could be involved in regionalizing the stomach.25Gao N. LeLay J. Vatamaniuk M.Z. et al.Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development.Genes Dev. 2008; 22: 3435-3448Crossref PubMed Scopus (0) Google Scholar Gata4 and Gata6 are involved in the specification of the extraembryonic endoderm28Kuo C.T. Morrisey E.E. Anandappa R. et al.GATA4 transcription factor is required for ventral morphogenesis and heart tube formation.Genes Dev. 1997; 11: 1048-1060Crossref PubMed Google Scholar, 29Molkentin J.D. Lin Q. Duncan S.A. et al.Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis.Genes Dev. 1997; 11: 1061-1072Crossref PubMed Google Scholar, 30Koutsourakis M. Langeveld A. Patient R. et al.The transcription factor GATA6 is essential for early extraembryonic development.Development. 1999; 126: 723-732Crossref Google Scholar and are expressed throughout the early definitive endoderm. During endodermal regionalization, both genes are expressed in the foregut. The expression domain of Gata4 is particularly interesting because its anterior boundary resides at the future forestomach/glandular stomach boundary. Potentially, Gata4 may have an important role in specifying the glandular stomach or specifying the forestomach vs the glandular stomach (Figure 2). Consistent with the idea that Gata4 is important for glandular stomach specification, Gata4 null cells do not appear to be able to adopt gastric identity in chimeric embryos when they are competing with wild-type cells.31Jacobsen C.M. Narita N. Bielinska M. et al.Genetic mosaic analysis reveals that GATA-4 is required for proper differentiation of mouse gastric epithelium.Dev Biol. 2002; 241: 34-46Crossref PubMed Scopus (0) Google Scholar Sox2 is expressed broadly throughout the foregut from the most anterior pharyngeal endoderm to the future boundary of gastric antrum and duodenum. Studies wherein expression of Sox2 is reduced in developing endoderm have shown that it helps govern the development of a number of foregut organs including the stomach, esophagus, trachea, and lung.32Que J. Luo X. Schwartz R.J. et al.Multiple roles for Sox2 in the developing and adult mouse trachea.Development. 2009; 136: 1899-1907Crossref PubMed Scopus (0) Google Scholar, 33Que J. Okubo T. Goldenring J.R. et al.Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm.Development. 2007; 134: 2521-2531Crossref PubMed Scopus (0) Google Scholar Such experiments involved hypomorphic animals, so it will be interesting to know what the effects of complete loss of SOX2 from early endoderm might be. Perhaps SOX2 has an even more critical role in anterior foregut and stomach specification than currently thought. The border between Sox2 and Cdx2 expression during development (Figure 2) resides at the prospective gastrointestinal junction and suggests that Sox2 could define this boundary. Misexpressing Sox2 in Cdx2-positive progenitors in the developing intestine increases expression of gastric-specific differentiation markers.34Raghoebir L. Bakker E.R. Mills J.C. et al.SOX2 redirects the developmental fate of the intestinal epithelium toward a premature gastric phenotype.J Mol Cell Biol. 2012; 4: 377-385Crossref PubMed Scopus (0) Google Scholar Interestingly, loss of Cdx2 during early development causes a dramatic transformation of the prospective intestine into Sox2-expressing esophageal-like progenitors and not gastric progenitors,35Gao N. White P. Kaestner K.H. Establishment of intestinal identity and epithelial-mesenchymal signaling by Cdx2.Dev Cell. 2009; 16: 588-599Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar indicating that SOX2 is not a simple progastric, anti-intestine transcription factor. Indeed, SOX2 levels are high in both adult esophagus and adult stomach.36Chen X. Qin R. Liu B. et al.Multilayered epithelium in a rat model and human Barrett's esophagus: similar expression patterns of transcription factors and differentiation markers.BMC Gastroenterol. 2008; 8: 1Crossref PubMed Scopus (0) Google Scholar Pdx1 is expressed regionally within the posterior foregut in the areas that give rise to the posterior stomach (antrum/pylorus), anterior duodenum, dorsal and ventral pancreatic buds, and proximal extrahepatic biliary system.27Offield M.F. Jetton T.L. Labosky P.A. et al.PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum.Development. 1996; 122: 983-995Crossref PubMed Google Scholar, 37Nomura S. Settle S.H. Leys C.M. et al.Evidence for repatterning of the gastric fundic epithelium associated with Menetrier's disease and TGFalpha overexpression.Gastroenterology. 2005; 128: 1292-1305Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Pdx1 expression can be used during development to distinguish antral gastric progenitors (SOX2+GATA4+PDX1+) from corpus progenitors (SOX2+GATA4+PDX1-). Loss of Pdx1 causes aberrant antral stomach progenitors including pyloric defects27Offield M.F. Jetton T.L. Labosky P.A. et al.PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum.Development. 1996; 122: 983-995Crossref PubMed Google Scholar and loss of gastrin-producing endocrine cells.38Larsson L.I. Madsen O.D. Serup P. et al.Pancreatic-duodenal homeobox 1-role in gastric endocrine patterning.Mech Dev. 1996; 60: 175-184Crossref PubMed Scopus (0) Google Scholar Hnf1β is expressed in the early endoderm and implicated in stomach specification. Definitive endoderm-specific knockout of Hnf1β alters gene expression within caudal stomach progenitors, including causing loss of Pdx1 and Indian hedgehog (Ihh).39Haumaitre C. Barbacci E. Jenny M. et al.Lack of TCF2/vHNF1 in mice leads to pancreas agenesis.Proc Natl Acad Sci U S A. 2005; 102: 1490-1495Crossref PubMed Scopus (0) Google Scholar The impact on gastric specification in these knockouts remains unclear, but recent in vitro studies intriguingly have implicated Hnf1β in promoting antral stomach specification in organoid culture.40McCracken K.W. Cata E.M. Crawford C.M. et al.Modelling human development and disease in pluripotent stem-cell-derived gastric organoids.Nature. 2014; 516: 400-404Crossref PubMed Scopus (95) Google Scholar To date, no specific gene has been shown to have expression restricted only to early gastric progenitors; thus, it remains difficult to examine directly how the stomach is specified from other organs, the way, for example, Cdx1 and Cdx2 have been studied in intestinal specification. Instead, investigators rely on more broadly expressed genes (ie, expressed concomitantly in other organs besides the stomach) such as Sox2, Gata4, and Pdx1 to identify the factors defining the prospective gastric regions. Further identification of transcripts that may have more restricted or specific expression to gastric progenitors (particularly to the glandular stomach) during early development could lead to the generation of new genetic tools to explore and characterize gastric specification or even to perform stomach-specific epithelial cell gene deletion because intestinal epithelial-specific deletion can be driven by Villin-Cre. However, there could be marked improvement in our understanding of stomach specification simply by manipulating gene expression in early endoderm with tools that already exist. For example, signaling pathways and transcription factors suspected of being involved in gastric development could be deleted via crosses to well-characterized mouse pedigrees that express Foxa3-, Sox17-, or Shh- Cre.41Lee C.S. Sund N.J. Behr R. et al.Foxa2 is required for the differentiation of pancreatic alpha-cells.Dev Biol. 2005; 278: 484-495Crossref PubMed Scopus (0) Google Scholar, 42Choi E. Kraus M.R. Lemaire L.A. et al.Dual lineage-specific expression of Sox17 during mouse embryogenesis.Stem Cells. 2012; 30: 2297-2308Crossref PubMed Scopus (16) Google Scholar, 43Harfe B.D. Scherz P.J. Nissim S. et al.Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities.Cell. 2004; 118: 517-528Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar Summing up all that currently is known and can be inferred from published studies, we have proposed one possible signaling and epistasis model for specification of glandular stomach (Figure 2). Regionalization throughout the luminal gastrointestinal tract depends in large part on epithelial–mesenchymal cross-talk, and the stomach does not seem to be an exception. For example, foundational experiments in chicks have shown that placing proventricular (stomach region in chicks similar to the mammalian glandular stomach) mesenchyme with gizzard (anterior chicken stomach) or esophageal endoderm induces proventricular gene expression and causes gland development in these normally nonglandular tissues.44Hayashi K. Yasugi S. Mizuno T. Pepsinogen gene transcription induced in heterologous epithelial-mesenchymal recombinations of chicken endoderms and glandular stomach mesenchyme.Development. 1988; 103: 725-731PubMed Google Scholar, 45Urase K. Fukuda K. Ishii Y. et al.Analysis of mesenchymal influence on the pepsinogen gene expression in the epithelium of chicken embryonic digestive tract.Rouxs Arch Dev Biol. 1996; 205: 382-390Crossref Scopus (0) Google Scholar Similarly, gizzard or esophageal mesenchyme can suppress proventricular gene expression and gland development in proventricular endoderm and promote squamous fates.46Takiguchi K. Yasugi S. Mizuno T. Gizzard epithelium of chick-embryos can express embryonic pepsinogen antigen, a marker protein of proventriculus.Rouxs Arch Dev Biol. 1986; 195: 475-483Crossref Scopus (0) Google Scholar Interestingly, proventricular mesenchyme could not induce proventricular gene expression in intestinal endoderm47Yasugi S. Matsushita S. Mizuno T. Gland formation induced in the allantoic and small intestinal endoderm by the proventricular mesenchyme is not coupled with pepsinogen expression.Differentiation. 1985; 30: 47-52Crossref Google Scholar; hence, overlying mesoderm can instruct endoderm identity but only within restricted regions. BMP factors have been implicated in promoting proventricular identity.48Narita T. Saitoh K. Kameda T. et al.BMPs are necessary for stomach gland formation in the chicken embryo: a study using virally induced BMP-2 and Noggin expression.Development. 2000; 127: 981-988Crossref PubMed Google Scholar Although BMP signaling, principally deriving from the mesenchyme, influences gastric epithelial development, Hedgehog signaling derived from the epithelium influences the mesenchyme. For example, in addition to their early role in foregut growth, Hedgehog (Shh/Ihh) signals are produced by the gastric endoderm to support mesenchymal growth and differentiation, a pattern that is maintained in the adult.49Ramalho-Santos M. Melton D.A. McMahon A.P. Hedgehog signals regulate multiple aspects of gastrointestinal development.Development. 2000; 127: 2763-2772Crossref PubMed Google Scholar, 50El-Zaatari M. Saqui-Salces M. Waghray M. et al.Sonic hedgehog in gastric physiology and neoplastic transformation: friend or foe?.Curr Opin Endocrinol Diabetes Obes. 2009; 16: 60-65Crossref PubMed Scopus (0) Google Scholar Another example of a factor that originates from the mesenchyme and regulates the epithelium is FGF10, likely via the FGF receptor 2B.51Spencer-Dene B. Sala F.G. Bellusci S. et al.Stomach development is dependent on fibroblast growth factor 10/fibroblast growth factor receptor 2b-mediated signaling.Gastroenterology. 2006; 130: 1233-1244Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar FGF10 promotes epithelial proliferation and gland development.51Spencer-Dene B. Sala F.G. Bellusci S. et al.Stomach development is dependent on fibroblast growth factor 10/fibroblast growth factor receptor 2b-mediated signaling.Gastroenterology. 2006; 130: 1233-1244Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 52Nyeng P. Norgaard G.A. Kobberup S. et al.FGF10 signaling controls stomach morphogenesis.Dev Biol. 2007; 303: 295-310Crossref PubMed Scopus (0) Google Scholar Although it may not be required for adult homeostasis, it has been shown to inhibit parietal and chief cell differentiation in favor of the mucous neck cell type.53Speer A.L. Al Alam D. Sala F.G. et al.Fibroblast growth factor 10-fibroblast growth factor receptor 2b mediated signaling is not required for adult glandular stomach homeostasis.PLoS One. 2012; 7: e49127Crossref PubMed Scopus (0) Google Scholar In addition to the themes of epithelial Hedgehog and mesenchymal BMP signaling that occur throughout the gastrointestinal tract, there have been some descriptions of signals more specific to gastric development vs other regions. For example, Barx1 is a transcription factor that is restricted to the prospective esophageal and gastric mesoderm. Barx1 null mice have significantly altered stomach morphology with disrupted patterning of the stomach. The stomach–intestinal boundary is disturbed such that ectopic CDX2+ intestinal epithelial cells can be found in the posterior stomach.54Kim B.M. Buchner G. Miletich I. et al.The stomach mesenchymal transcription factor Barx1 specifies gastric epithelial identity through inhibition of transient Wnt signaling.Dev Cell. 2005; 8: 611-622Abstract Full Text Full Text PDF PubMed Scopus (0) Google Sc