title: Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis.
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.
authors.affiliation: Department of Genetics and Development, Columbia University, New York, New York 10032, USA.
authors.forename: Shouhong
authors.initials: S
authors.lastname: Xuan
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Borok
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Decker
authors.forename: Michele A
authors.initials: MA
authors.lastname: Battle
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Duncan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hale
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Macdonald
authors.forename: Lori
authors.initials: L
authors.lastname: Sussel
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis; D001665:Binding Sites; D043422:Carboxypeptidases A / Q000032:analysis; D002454:Cell Differentiation; D002455:Cell Division; D019070:Cell Lineage; D004195:Disease Models, Animal; D004707:Endoderm / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology; D050991:GATA4 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050993:GATA6 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D055785:Gene Knockdown Techniques; D005838:Genotype; D005865:Gestational Age; D006943:Hyperglycemia / Q000151:congenital / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D051379:Mice; D009419:Nerve Tissue Proteins / Q000032:analysis; D009928:Organ Specificity; D038081:Organogenesis / Q000235:genetics*; D010179:Pancreas / Q000002:abnormalities / Q000196:embryology* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D043422:Carboxypeptidases A; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; D007328:Insulin; D009419:Nerve Tissue Proteins; C484171:Gata4 protein, mouse; C494760:Gata6 protein, mouse; C407737:Neurog3 protein, mouse