TY - JOUR
T1 - Genetic mosaic analysis reveals that GATA-4 is required for proper differentiation of mouse gastric epithelium
AU - Jacobsen, Christina M.
AU - Narita, Naoko
AU - Bielinska, Malgorzata
AU - Syder, Andrew J.
AU - Gordon, Jeffrey I.
AU - Wilson, David B.
N1 - Funding Information:
We thank J. Darnell, J. Harmony, A. McMahon, and T. Simon for providing cDNA probes, and Helka Parviainen and Markku Heikin-heimo for assistance with immunohistochemistry. This research was supported by grants from the NIH (P50 HL61006, DK58529), AHA, and Sigrid Juselius Foundation. C.M.J. was supported by institutional training grant T32-HL07873 from the NIH. Chimeric mice were generated in the NIH-supported Washington University Department of Pediatrics CHRC Genetically Altered Mouse Core. The Digestive Diseases Research Core Center (DK 52574) also supported this work.
PY - 2002/1/1
Y1 - 2002/1/1
N2 - 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-l- 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-β superfamily.
AB - 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-l- 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-β superfamily.
KW - Endoderm
KW - H, K-ATPase
KW - Sonic hedgehog
KW - Stomach
KW - Transcription factor
UR - http://www.scopus.com/inward/record.url?scp=0036149471&partnerID=8YFLogxK
U2 - 10.1006/dbio.2001.0424
DO - 10.1006/dbio.2001.0424
M3 - Article
C2 - 11784093
AN - SCOPUS:0036149471
SN - 0012-1606
VL - 241
SP - 34
EP - 46
JO - Developmental Biology
JF - Developmental Biology
IS - 1
ER -