Genetic Mosaic Analysis Reveals That GATA-4 Is Required for Proper Differentiation of Mouse Gastric Epithelium

Abstract

During mouse embryogenesis GATA-4 is expressed first in primitive endoderm and then in definitive endoderm derivatives, including glandular stomach and intestine. To explore the role of GATA-4 in specification of definitive gastric endoderm, we generated chimeric mice by introducing Gata4(-/-) ES cells into ROSA26 morulae or blastocysts. In E14.5 chimeras, Gata4(-/-) cells were represented in endoderm lining the proximal and distal stomach. These cells expressed early cytodifferentiation markers, including GATA-6 and ApoJ. However, by E18.5, only rare patches of Gata4(-/-) epithelium were evident in the distal stomach. This heterotypic epithelium had a squamous morphology and did not express markers associated with differentiation of gastric epithelial cell lineages. Sonic Hedgehog, an endoderm-derived signaling molecule normally down-regulated in the distal stomach, was overexpressed in Gata4(-/-) cells. We conclude that GATA-4-deficient cells have an intrinsic defect in their ability to differentiate. Similarities in the phenotypes of Gata4(-/-) chimeras and mice with other genetically engineered mutations that affect gut development suggest that GATA-4 may be involved in the gastric epithelial response to members of the TGF-beta superfamily.

GATA‐4:FOG interactions regulate gastric epithelial development in the mouse

“…2E,F,I,J). This altered expression pattern of Shh in Gata4 ki/ki mice mirrored that reported in Gata4 -/-chimeric mice (Jacobsen et al, 2002), suggesting that a GATA-4: FOG interaction lies downstream of activin receptor-mediated signals and serves to attenuate Shh expression in the developing hindstomach.…”

“…Previous studies have shown that GATA-4 is expressed in hindstomach epithelial cells throughout fetal and postnatal development and localizes in pit, neck, and parietal cells in the mature glandular epithelium (Jacobsen et al, 2002;Nemer and Nemer, 2003). FOG-1 expression has been documented in hematopoietic progenitors, gonadal cells, and the heart (Tsang et al, 1997;Tevosian et al, 2002;Katz et al, 2003;Gitler et al, 2003), while FOG-2 has been detected in brain, gonadal somatic cells, and cardiac tissue (Tsang et al, 1997(Tsang et al, , 1998Svensson et al, 1999;Tevosian et al, 1999;Lu et al, 1999;Anttonen et al, 2003).…”

“…In vitro studies have shown that GATA-4 (or the closely related factors GATA-5 and -6) can bind and trans-activate several genes expressed in differentiating and terminally differentiated members of the parietal and zymogenic cell lineages (Tamura et al, 1993;Mushiake et al, 1994;Nishi et al, 1997;Sakamoto et al, 1998Sakamoto et al, , 2000, and studies with chimeric mice underscore the in vivo contributions of GATA-4 to expression of these genes (Jacobsen et al, 2002). In vitro, FOGs can either enhance or repress the activity of GATA-4, depending on the promoter studied (Lu et al, 1999;Viger, 2001, 2003;Lin et al, 2004).…”

“…GATA-4, a transcription factor expressed in hindstomach epithelium, is a key participant in the differentiation of this segment of the gut (Jacobsen et al, 2002). Gata4 null mice die by E9.5, so insights into gut morphogenesis cannot be ascertained from these animals (Kuo et al, 1997;Molkentin et al, 1997;Narita et al, 1997b;Watt et al, 2004).…”

“…Gata4 null mice die by E9.5, so insights into gut morphogenesis cannot be ascertained from these animals (Kuo et al, 1997;Molkentin et al, 1997;Narita et al, 1997b;Watt et al, 2004). In chimeric mice, Gata4 -/-cells can contribute to invaginating foregut epithelium, but these cells exhibit deregulated gene expression and impaired epithelial-mesenchymal signaling (Jacobsen et al, 2002). At later stages of fetal development, GATA-4-deficient cells display a cell autonomous defect in their ability to differentiate into parietal cells and other gastric epithelial lineages (Jacobsen et al, 2002).…”