Pdx1 regulates pancreas tubulogenesis and E-cadherin expression

Leilani Marty-Santos, Ondine Cleaver

Research output: Contribution to journalArticle

22 Scopus citations

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 languageEnglish (US)
Pages (from-to)101-112
Number of pages12
JournalDevelopment (Cambridge)
Volume143
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • Cdh1
  • E-cadherin
  • Endocrine
  • Epithelium
  • Lumen diameter
  • Microlumen
  • Pancreatic bud
  • Pdx1
  • pMLC
  • Stratification
  • β-catenin

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology

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