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Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis. J Clin Invest 2012 Oct;122(10):3516-28

Date

09/26/2012

Pubmed ID

23006325

Pubmed Central ID

PMC3461916

DOI

10.1172/JCI63352

Scopus ID

2-s2.0-84867174750   103 Citations

Abstract

Pancreatic agenesis is a human disorder caused by defects in pancreas development. To date, only a few genes have been linked to pancreatic agenesis in humans, with mutations in pancreatic and duodenal homeobox 1 (PDX1) and pancreas-specific transcription factor 1a (PTF1A) reported in only 5 families with described cases. Recently, mutations in GATA6 have been identified in a large percentage of human cases, and a GATA4 mutant allele has been implicated in a single case. In the mouse, Gata4 and Gata6 are expressed in several endoderm-derived tissues, including the pancreas. To analyze the functions of GATA4 and/or GATA6 during mouse pancreatic development, we generated pancreas-specific deletions of Gata4 and Gata6. Surprisingly, loss of either Gata4 or Gata6 in the pancreas resulted in only mild pancreatic defects, which resolved postnatally. However, simultaneous deletion of both Gata4 and Gata6 in the pancreas caused severe pancreatic agenesis due to disruption of pancreatic progenitor cell proliferation, defects in branching morphogenesis, and a subsequent failure to induce the differentiation of progenitor cells expressing carboxypeptidase A1 (CPA1) and neurogenin 3 (NEUROG3). These studies address the conserved and nonconserved mechanisms underlying GATA4 and GATA6 function during pancreas development and provide a new mouse model to characterize the underlying developmental defects associated with pancreatic agenesis.

Author List

Xuan S, Borok MJ, Decker KJ, Battle MA, Duncan SA, Hale MA, Macdonald RJ, Sussel L

Author

Michele A. Battle PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Basic Helix-Loop-Helix Transcription Factors
Binding Sites
Carboxypeptidases A
Cell Differentiation
Cell Division
Cell Lineage
Disease Models, Animal
Endoderm
Epithelial Cells
GATA4 Transcription Factor
GATA6 Transcription Factor
Gene Expression Regulation, Developmental
Gene Knockdown Techniques
Genotype
Gestational Age
Hyperglycemia
Insulin
Mice
Nerve Tissue Proteins
Organ Specificity
Organogenesis
Pancreas
Transcription, Genetic