NRAGE: a potential rheostat during branching morphogenesis.
Branching morphogenesis is a developmental process characteristic of many organ systems. Specifically, during renal branching morphogenesis, its been postulated that the final number of nephrons formed is one key clinical factor in the development of hypertension in adulthood. As it has been established that BMPs regulate, in part, renal activity of p38 MAP kinase (p38(MAPK)) and it has demonstrated that the cytoplasmic protein Neurotrophin Receptor MAGE homologue (NRAGE) augments p38(MAPK) activation, it was hypothesized that a decrease in the expression of NRAGE during renal branching would result in decreased branching of the UB that correlated with changes in p38(MAPK) activation. To verify this, the expression of NRAGE was reduced in ex vivo kidney explants cultures using antisense morpholino. Morpholino treated ex vivo kidney explants expression were severely stunted in branching, a trait that was rescued with the addition of exogenous GDNF. Renal explants also demonstrated a precipitous drop in p38(MAPK) activation that too was reversed in the presence of recombinant GDNF. RNA profiling of NRAGE diminished ex vivo kidney explants resulted in altered expression of GDNF, Ret, BMP7 and BMPRIb mRNAs. Our results suggested that in early kidney development NRAGE might have multiple roles during renal branching morphogenesis through association with both the BMP and GDNF signaling pathways.
Nikopoulos
George N
GN
Maine Medical Center Research Institute, Center for Molecular Medicine, Scarborough, ME 04074, USA.
Martins
Joao Ferreira
JF
Adams
Tamara L
TL
Karaczyn
Aldona
A
Adams
Derek
D
Vary
Calvin
C
Oxburgh
Leif
L
Verdi
Joseph M
JM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000196:embryology* / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009024:Morphogenesis / Q000187:drug effects; D009363:Neoplasm Proteins / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014513:Ureter / Q000187:drug effects / Q000196:embryology / Q000201:enzymology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018398:Homeodomain Proteins; C093253:Hoxb7 protein, mouse; C486541:Maged1 protein, mouse; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D048051:p38 Mitogen-Activated Protein Kinases