Journal Article

Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis

Macdonald, Raymond J., Battle, Michele A., Duncan, Stephen A., Borok, Matthew J., Decker, Kimberly J., Sussel, Lori, Hale, Michael A., Xuan, Shouhong

2012

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Agenesis / Animals / Basic Helix-Loop-Helix Transcription Factors - analysis / Binding Sites / Biomedical research / Carboxypeptidases A - analysis / Cell Differentiation / Cell Division / Cell Lineage / Disease Models, Animal / Endoderm - metabolism / Enzymes / Epithelial Cells - pathology / GATA4 Transcription Factor - deficiency / GATA4 Transcription Factor - genetics / GATA4 Transcription Factor - physiology / GATA6 Transcription Factor - deficiency / GATA6 Transcription Factor - genetics / GATA6 Transcription Factor - physiology / Gene Expression Regulation, Developmental - genetics / Gene Knockdown Techniques / Gene mutations / Genetic aspects / Genotype / Gestational Age / Health aspects / Heart / Hyperglycemia - congenital / Hyperglycemia - genetics / Insulin - metabolism / Insulin Secretion / Mice / Morphogenesis / Mutation / Nerve Tissue Proteins - analysis / Organ Specificity / Organogenesis - genetics / Pancreas / Pancreas - abnormalities / Pancreas - embryology / Pancreas - pathology / Physiological aspects / Risk factors / Transcription factors / Transcription, Genetic