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 endodermderived 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.

GATA4 and GATA6 regulate pancreatic endoderm identity through inhibition of hedgehog signaling

“…2V-Y′). At E18.5, conversion of the Pdx1 lineage to mature stomach fates is widespread and many of the Tomato lineagelabeled cells have become incorporated into the stomach epithelium as previously demonstrated (Xuan, et al, 2012) where they coexpress mature stomach markers, including MUC5AC and ATP4B (Fig. S2).…”

“…Simultaneous deletion of Gata4 and Gata6 in the pancreatic progenitor domain resulted in severely aplastic pancreatic buds (Carrasco et al, 2012;Xuan et al, 2012). To characterize the molecular pathways that function downstream of GATA4 and GATA6 to mediate the regulation of pancreatic differentiation and morphogenesis, we performed genome-wide transcriptome analysis of the arrested pancreatic rudiments from pDKO embryos compared with littermate control embryos.…”

“…In the pancreas, Gata4 and Gata6 have overlapping expression in the pancreatic endoderm, but gradually become expressed in separate domains: Gata4 becomes restricted to the exocrine compartment and Gata6 is predominantly expressed in the endocrine compartment (Decker et al, 2006;Ketola et al, 2004). Using a Cre-lox approach, we previously demonstrated that simultaneous deletion of Gata4 and Gata6 from pancreatic progenitor cells leads to pancreatic agenesis in newborn mice (Carrasco et al, 2012;Xuan et al, 2012). The importance of GATA4 and GATA6 in human pancreas development has also been highlighted in reports of genetic cases of human pancreatic agenesis: GATA6 haploinsufficiency contributes to the majority of pancreatic agenesis cases (Lango Allen et al, 2012), and GATA4 haploinsufficiency has been documented in a small number of patients with pancreatic agenesis (Shaw-Smith et al, 2014).…”

Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

“…[124][125][126] In mice, 2 genetic studies that inactivated Gata4 or Gata6 in embryonic MPCs using Cre/LoxP technology induced minor derangements in pancreatic cell morphology that resolved postnatally whereas the loss of both Gata4 and Gata6 led to pancreatic agenesis at birth (Table 1). 127,128 Further, mice with pancreatic ablation of both Gata4 alleles and one Gata6 allele had less acinar cells. Pdx1 was identified as a direct target of Gata proteins.…”

“…Present in foregut endoderm, dorsal and ventral epithelium and later restricted to acinar cells [127][128] Gata6 Present in foregut endoderm, dorsal and ventral epithelium and later restricted to endocrine and ductal cells [127][128] Secondary (e12.5-16.5) and tertiary (e16.5-postnatal) transitions Ngn3…”