title: Endothelium-derived Netrin-4 supports pancreatic epithelial cell adhesion and differentiation through integrins α2β1 and α3β1.
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.
  
  
  RESULTS
  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 α2β1 and 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
  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.
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Mayra
authors.initials: M
authors.lastname: Yebra
authors.forename: Giuseppe R
authors.initials: GR
authors.lastname: Diaferia
authors.forename: Anthony M P
authors.initials: AM
authors.lastname: Montgomery
authors.forename: Thomas
authors.initials: T
authors.lastname: Kaido
authors.forename: William J
authors.initials: WJ
authors.lastname: Brunken
authors.forename: Manuel
authors.initials: M
authors.lastname: Koch
authors.forename: Gary
authors.initials: G
authors.lastname: Hardiman
authors.forename: Laura
authors.initials: L
authors.lastname: Crisa
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cirulli
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005934:Glucagon / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D039201:Integrin alpha3beta1 / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D000075385:Netrins; D020411:Oligonucleotide Array Sequence Analysis; D010183:Pancreatic Ducts / Q000166:cytology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D007328:Insulin; D038982:Integrin alpha2beta1; D039201:Integrin alpha3beta1; C498815:NTN4 protein, human; D009414:Nerve Growth Factors; D000075385:Netrins; D012333:RNA, Messenger; D005934:Glucagon