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GATA4 and GATA6 control mouse pancreas organogenesis
Manuel Carrasco, … , Francisco Martín, Anabel Rojas
Manuel Carrasco, … , Francisco Martín, Anabel Rojas
Published September 24, 2012
Citation Information: J Clin Invest. 2012;122(10):3504-3515. https://doi.org/10.1172/JCI63240.
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Research Article

GATA4 and GATA6 control mouse pancreas organogenesis

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Abstract

Recently, heterozygous mutations in GATA6 have been found in neonatal diabetic patients with failed pancreatic organogenesis. To investigate the roles of GATA4 and GATA6 in mouse pancreas organogenesis, we conditionally inactivated these genes within the pancreas. Single inactivation of either gene did not have a major impact on pancreas formation, indicating functional redundancy. However, double Gata4/Gata6 mutant mice failed to develop pancreata, died shortly after birth, and displayed hyperglycemia. Morphological defects in Gata4/Gata6 mutant pancreata were apparent during embryonic development, and the epithelium failed to expand as a result of defects in cell proliferation and differentiation. The number of multipotent pancreatic progenitors, including PDX1+ cells, was reduced in the Gata4/Gata6 mutant pancreatic epithelium. Remarkably, deletion of only 1 Gata6 allele on a Gata4 conditional knockout background severely reduced pancreatic mass. In contrast, a single WT allele of Gata4 in Gata6 conditional knockout mice was sufficient for normal pancreatic development, indicating differential contributions of GATA factors to pancreas formation. Our results place GATA factors at the top of the transcriptional network hierarchy controlling pancreas organogenesis.

Authors

Manuel Carrasco, Irene Delgado, Bernat Soria, Francisco Martín, Anabel Rojas

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Figure 1

Single inactivation of Gata4 and Gata6 does not affect pancreas formation.

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Single inactivation of Gata4 and Gata6 does not affect pancreas formatio...
(A–D) Immunohistochemical analyses show strong expression of GATA4 in acinar cells (arrowheads in A) and GATA6 in endocrine cells (arrows in C) in pancreatic sections of control mice at P1. Loss of GATA4 (B, arrowheads) and GATA6 (D, arrows) in newborn conditional mutant mice is confirmed by immunohistochemical analysis. (E–G) Gross morphology of neonatal WT and conditional mutant guts. H&E-stained sections of newborn control (H), Gata4 (I), and Gata6 (J) conditional knockout pancreata does not reveal major defects in pancreas architecture. Mature acinar (amylase), ductal (mucin) (K–M), and islet (insulin and glucagon) markers (N–P) are normally expressed in single Gata4 and Gata6 conditional knockout mice. Insets in H–M show higher magnification of acinar cells. Mild ductal dilation in acinar cells of Gata4flox/flox;Pdx1-Cre is observed (I and L, insets). Nuclei are counterstained with DAPI in K–P. Scale bars: 50 μm; 25 μm (insets).

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