Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1.
Branching of ureteric bud-derived epithelial tubes is a key morphogenetic process that shapes development of the kidney. Glial cell line-derived neurotrophic factor (GDNF) initiates ureteric bud formation and promotes subsequent branching morphogenesis. Exactly how GDNF coordinates branching morphogenesis is unclear. Here we show that the absence of the receptor tyrosine kinase antagonist Sprouty1 (Spry1) results in irregular branching morphogenesis characterized by both increased number and size of ureteric bud tips. Deletion of Spry1 specifically in the epithelium is associated with increased epithelial Wnt11 expression as well as increased mesenchymal Gdnf expression. We propose that Spry1 regulates a Gdnf/Ret/Wnt11-positive feedback loop that coordinates mesenchymal-epithelial dialogue during branching morphogenesis. Genetic experiments indicate that the positive (GDNF) and inhibitory (Sprouty1) signals have to be finely balanced throughout renal development to prevent hypoplasia or cystic hyperplasia. Epithelial cysts develop in Spry1-deficient kidneys that share several molecular characteristics with those observed in human disease, suggesting that Spry1 null mice may be useful animal models for cystic hyperplasia.
Basson
M Albert
MA
Division of Hematology/Oncology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Watson-Johnson
Judy
J
Shakya
Reena
R
Akbulut
Simge
S
Hyink
Deborah
D
Costantini
Frank D
FD
Wilson
Patricia D
PD
Mason
Ivor J
IJ
Licht
Jonathan D
JD
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D004195:Disease Models, Animal; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology*; D006965:Hyperplasia; D007668:Kidney / Q000196:embryology* / Q000473:pathology; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D014513:Ureter / Q000196:embryology* / Q000473:pathology; D019459:Urothelium / Q000196:embryology / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008565:Membrane Proteins; D010750:Phosphoproteins; C425468:Spry1 protein, mouse