Endothelium-derived Netrin-4 supports pancreatic epithelial cell adhesion and differentiation through integrins α2β1 and α3β1

Mayra Yebra, Giuseppe R. Diaferia, Anthony M P Montgomery, Thomas Kaido, William J. Brunken, Manuel Koch, Gary Hardiman, Laura Crisa, Vincenzo Cirulli

Research output: Contribution to journalArticle

Abstract

Background: Netrins have been extensively studied in the developing central nervous system as pathfinding guidance cues, and more recently in non-neural tissues where they mediate cell adhesion, migration and differentiation. Netrin-4, a distant relative of Netrins 1-3, has been proposed to affect cell fate determination in developing epithelia, though receptors mediating these functions have yet to be identified. Methodology/Principal Findings: Using human embryonic pancreatic cells as a model of developing epithelium, here we report that Netrin-4 is abundantly expressed in vascular endothelial cells and pancreatic ductal cells, and supports epithelial cell adhesion through integrins α2β1and α3β1. Interestingly, we find that Netrin-4 recognition by embryonic pancreatic cells through integrins α2β1 and α3β1 promotes insulin and glucagon gene expression. In addition, full genome microarray analysis revealed that fetal pancreatic cell adhesion to Netrin-4 causes a prominent down-regulation of cyclins and up-regulation of negative regulators of the cell cycle. Consistent with these results, a number of other genes whose activities have been linked to developmental decisions and/or cellular differentiation are up-regulated. Conclusions/Significance: Given the recognized function of blood vessels in epithelial tissue morphogenesis, our results provide a mechanism by which endothelial-derived Netrin-4 may function as a pro-differentiation cue for adjacent developing pancreatic cell populations expressing adhesion receptors α2β1 and α3β1 integrins.

Original languageEnglish
Article numbere22750
JournalPLoS One
Volume6
Issue number7
DOIs
Publication statusPublished - 2011

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Cell adhesion
integrins
endothelium
cell adhesion
Cell Adhesion
Integrins
cell differentiation
Endothelium
Cell Differentiation
epithelial cells
Epithelial Cells
Genes
Cells
epithelium
Epithelium
Tissue
Cyclins
blood vessels
Endothelial cells
Blood vessels

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Endothelium-derived Netrin-4 supports pancreatic epithelial cell adhesion and differentiation through integrins α2β1 and α3β1. / Yebra, Mayra; Diaferia, Giuseppe R.; Montgomery, Anthony M P; Kaido, Thomas; Brunken, William J.; Koch, Manuel; Hardiman, Gary; Crisa, Laura; Cirulli, Vincenzo.

In: PLoS One, Vol. 6, No. 7, e22750, 2011.

Research output: Contribution to journalArticle

Yebra, Mayra ; Diaferia, Giuseppe R. ; Montgomery, Anthony M P ; Kaido, Thomas ; Brunken, William J. ; Koch, Manuel ; Hardiman, Gary ; Crisa, Laura ; Cirulli, Vincenzo. / Endothelium-derived Netrin-4 supports pancreatic epithelial cell adhesion and differentiation through integrins α2β1 and α3β1. In: PLoS One. 2011 ; Vol. 6, No. 7.
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