Loss of GATA4 causes ectopic pancreas in the stomach

Abstract

Pancreatic heterotopia is defined as pancreatic tissue outside its normal location in the body and anatomically separated from the pancreas. In this work we have analyzed the stomach glandular epithelium of Gata4 flox/flox; Pdx1‐Cre mice (Gata4KO mice). We found that Gata4KO glandular epithelium displays an atypical morphology similar to the cornified squamous epithelium and exhibits upregulation of forestomach markers. The developing gastric units fail to form properly, and the glandular epithelial cells do not express markers of gastric gland in the absence of GATA4. Of interest, the developing glands of the Gata4KO stomach express pancreatic cell markers. Furthermore, a mass of pancreatic tissue located in the subserosa of the Gata4KO stomach is observed at adult stages. Heterotopic pancreas found in Gata4‐deficient mice contains all three pancreatic cell lineages: ductal, acinar, and endocrine. Moreover, Gata4 expression is downregulated in ectopic pancreatic tissue of some human biopsy samples. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma

“…Gata4 and Gata6 also share partially redundant functions during pancreas organogenesis, since concomitant inactivation results in pancreas agenesis while inactivation of only one of them does not impede pancreas formation[23,24]. Gata4 inactivation in the Pdx1-expressing domain during mouse development results in pancreatic heterotopia in the stomach[25]. Accordingly, GATA4 and GATA6 control shared developmental programmes but also have gene-specific functions.…”

GATA4 regulates epithelial morphogenesis in the developing mouse stomach to promote establishment of a glandular columnar epithelium

“…The zinc finger containing transcription factor GATA4 is critical for development of many GI organs, including the glandular stomach and small intestine, and is aberrantly expressed in BE and esophageal, gastric, and colorectal cancers (Dulak et al, 2012;Haveri et al, 2008;Jacobsen et al, 2002;Kohlnhofer et al, 2016;Miller et al, 2003;Rodríguez-Seguel et al, 2020;Stavniichuk et al, 2020;Thompson et al, 2017;Walker et al, 2014;Walker et al, 2014b). Between E8.5-E10.5 of mouse development, GATA4 is expressed throughout the caudal foregut endoderm (Jacobsen et al 2002;Rojas et al 2010;Watt et al 2007).…”

“…Moreover, histological characterization of chimeric mouse stomachs generated with wild-type and Gata4 -/-ES cells shows that GATA4-null regions display features of stratified epithelium and lose expression of parietal cell, zymogenic chief cell, and neck cell marker genes (Jacobsen et al 2002). Conditional elimination of GATA4 primarily in the distal region of the mouse stomach during late stages of development using PDX1-Cre results in an antrum expressing FS and pancreatic genes (Rodríguez-Seguel et al 2020). These two mouse models provide insight into the requirement of GATA4 during late stages of glandular stomach development.…”

GATA4 Controls Epithelial Morphogenesis in the Developing Stomach to Promote Establishment of Glandular Columnar Epithelium

“…[4][5][6][7][8][9][10] The zinc finger containing transcription factor GATA4 is critical for development of many GI organs, including the glandular stomach and small intestine, and is aberrantly expressed in BE and esophageal, gastric, and colorectal cancers. [11][12][13][14][15][16][17][18][19][20] Binding of GATA4's zinc finger domains to consensus (A/T) GATA(A/G) sequences in promoters and enhancers regulates gene expression. 21 Protein-protein interactions between GATA4 and other transcriptional regulators further influence tissue-specific and cell-specific gene expression programs.…”

“…27 Conditional GATA4 elimination primarily in the distal region of the mouse stomach during late stages of development using Pdx1-Cre results in an antrum expressing FS and pancreatic genes. 19 These mouse models provide insight into the requirement of GATA4 during late stages of glandular stomach development. The role of GATA4 during the earliest stages of foregut development, when domains with different epithelial structures are first delineated, however, has yet to be comprehensively determined.…”