Abstract
SummaryHeterozygous de novo mutations in GATA6 are the most frequent cause of pancreatic agenesis in humans. In mice, however, a similar phenotype requires the biallelic loss of Gata6 and its paralog Gata4. To elaborate the human-specific requirements for GATA6, we chose to model GATA6 loss in vitro by combining both gene-edited and patient-derived pluripotent stem cells (hPSCs) and directed differentiation toward β-like cells. We find that GATA6 heterozygous hPSCs show a modest reduction in definitive endoderm (DE) formation, while GATA6-null hPSCs fail to enter the DE lineage. Consistent with these results, genome-wide studies show that GATA6 binds and cooperates with EOMES/SMAD2/3 to regulate the expression of cardinal endoderm genes. The early deficit in DE is accompanied by a significant reduction in PDX1+ pancreatic progenitors and C-PEPTIDE+ β-like cells. Taken together, our data position GATA6 as a gatekeeper to early human, but not murine, pancreatic ontogeny.
Highlights
Pancreatic agenesis is an extremely rare human condition resulting from the impaired formation of the pancreas during embryonic development
In contrast to the mouse, complete loss of GATA6 abrogates definitive endoderm (DE) production. Consistent with these results, genome-wide studies show that GATA6 binds and cooperates with EOMES/SMAD2/3 to regulate the expression of cardinal endoderm genes
GATA6 Expression during Directed Differentiation of human pluripotent stem cells (hPSCs) into the Endocrine Lineage Consistent with Gata6 expression in the mouse embryo, we previously showed that GATA6 is activated during the early differentiation of human embryonic stem cells (hESCs) into the DE lineage (Teo et al, 2015; Vallier et al, 2009)
Summary
Pancreatic agenesis is an extremely rare human condition resulting from the impaired formation of the pancreas during embryonic development. Pdx transcripts label the incipient pancreatic primordium—two epithelial buds that are situated dorsally and ventrally on opposite sides of the posterior foregut around embryonic day 9.5 (Jørgensen et al, 2007; Pan and Wright, 2011). In Pdx1-null mutant mice, these buds initially form but quickly regress, resulting in complete pancreatic agenesis, severe hyperglycemia, and death within a few days of birth (Ahlgren et al., 1996; Jonsson et al, 1994; Offield et al, 1996). The pathology of human patients with homozygous or compound heterozygous mutations in PDX1 mirrors the agenesis phenotype observed in Pdx1-deficient mice (Schwitzgebel et al, 2003; Stoffers et al, 1997)
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