Pdx1 regulates pancreas tubulogenesis and E-cadherin expression

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.

Cellular and molecular mechanisms coordinating pancreas development

“…The importance of these transcription factors (TFs) is reflected by pancreatic agenesis in mice with homozygous mutation for Pdx1 or Ptf1a. However, initial buds are formed in these animals, indicating that we have still not identified the most upstream regulators of pancreatic bud initiation (Ahlgren et al, 1996;Jonsson et al, 1994;Marty-Santos and Cleaver, 2016;Offield et al, 1996). The absence of Pdx1 also results in defects in gastro-duodenal development, as Pdx1 is expressed broadly in the foregut endoderm at early stages of development and is not restricted to pancreatic buds.…”

Role of CD34 family members in lumen formation in the developing kidney

“…E10.5 pancreases were collected and embedded in paraffin as previously described [26, 27]. For nonparaffin sections, E14.5 and P0 kidneys were fixed for 2h in 4% PFA/PBS, and E10.5 pancreases were fixed in 4% PFA/PBS overnight 4°C.…”

Acinar cell plasticity and development of pancreatic ductal adenocarcinoma

“…As shown by lineage tracing, during mouse development, PDX1-positive cells represent progenitors of all mature pancreatic cell types 55 . PDX1 is involved in regulation of morphologic changes needed for branching morphogenesis during pancreas organogenesis 56,57 , but it is also required at a later stage in development for differentiation of islet β cells 58 and the formation of acinar tissue 59 . Transgenic persistent expression of PDX1 in mice leads to smaller pancreata, in which acinar cells are replaced by duct-like structures 60 .…”