Journal
STEM CELL REPORTS
Volume 12, Issue 1, Pages 57-70Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2018.12.003
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Funding
- EDB Singapore Childhood Undiagnosed Diseases Program grant
- A*STAR Strategic Positioning Fund (SPF) Genetic Orphan Diseases Adopted: Fostering Innovation Therapy (GODAFIT) grant
- ERC starting grant Relieve IMDs
- Wellcome Trust
- Medical Research Council [PSAG028]
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Heterozygous 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 13-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+ beta-like cells. Taken together, our data position GATA6 as a gatekeeper to early human, but not murine, pancreatic ontogeny.
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