Pdx1 regulates pancreas tubulogenesis and E-cadherin expression

Development. 2016 Jan 1;143(1):101-12. doi: 10.1242/dev.126755. Epub 2015 Dec 10.

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.

Keywords: Cdh1; E-cadherin; Endocrine; Epithelium; Lumen diameter; Microlumen; Pancreatic bud; Pdx1; Stratification; pMLC; β-catenin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actomyosin / metabolism
  • Animals
  • Binding Sites
  • Cadherins / biosynthesis*
  • Cadherins / metabolism
  • Cdh1 Proteins / metabolism
  • Cell Differentiation / genetics
  • Cell Line
  • Cell Proliferation / genetics
  • Diabetes Mellitus / embryology
  • Epithelium / embryology
  • Gene Expression Regulation, Developmental / genetics*
  • HEK293 Cells
  • Homeodomain Proteins / genetics*
  • Humans
  • Insulin-Secreting Cells / cytology*
  • Mice
  • Pancreas / abnormalities
  • Pancreas / embryology*
  • Promoter Regions, Genetic / genetics
  • Trans-Activators / genetics*
  • Transcriptional Activation / genetics
  • beta Catenin / biosynthesis

Substances

  • Cadherins
  • Cdh1 Proteins
  • Fzr1 protein, mouse
  • Homeodomain Proteins
  • Trans-Activators
  • beta Catenin
  • pancreatic and duodenal homeobox 1 protein
  • Actomyosin