Abstract
Current efforts in developing treatments for diabetes focus on in vitro generation of functional β-cells for cell replacement therapies; however, these attempts have only been partly successful because factors involved in islet formation remain incompletely understood. The embryonic pancreas, which gives rise to β-cells, undergoes early epithelial rearrangements, including transient stratification of an initially monolayered epithelium, followed by microlumen formation and later resolution into branches. Within the epithelium, a multipotent progenitor cell (MPC) population is specified, giving rise to three important lineages: acinar, ductal and endocrine. Pdx1 is a transcription factor required for pancreas development and lineage specification; however, few Pdx1 targets that regulate pancreatogenesis have been identified. We find that pancreatic defects in Pdx1−/− embryos initiate at the time when the progenitor pool is specified and the epithelium should resolve into branches. Pdx1−/− microlumen diameters expand aberrantly, resulting in failure of epithelial tubulogenesis and ductal plexus formation. Pdx1−/− epithelial cell proliferation is decreased and the MPC pool is rapidly lost. We identify two conserved Pdx1 binding sites in the epithelial cadherin (E-cad, Cdh1) promoter, and show that Pdx1 directly binds and activates E-cad transcription. In addition, Pdx1 is required in vivo for maintenance of E-cad expression, actomyosin complex activity and cell shape. These findings demonstrate a novel link between regulators of epithelial architecture, specification of pancreatic cell fate and organogenesis.
Original language | English (US) |
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Pages (from-to) | 101-112 |
Number of pages | 12 |
Journal | Development (Cambridge) |
Volume | 143 |
Issue number | 1 |
DOIs | |
State | Published - Jan 1 2016 |
Keywords
- Cdh1
- E-cadherin
- Endocrine
- Epithelium
- Lumen diameter
- Microlumen
- Pancreatic bud
- Pdx1
- Stratification
- pMLC
- β-catenin
ASJC Scopus subject areas
- Molecular Biology
- Developmental Biology