Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction.
Intercellular signaling molecules and their receptors, whose expression must be tightly regulated in time and space, coordinate organogenesis. Regulators of intracellular signaling pathways provide an additional level of control. Here we report that loss of the receptor tyrosine kinase (RTK) antagonist, Sprouty1 (Spry1), causes defects in kidney development in mice. Spry1(-/-) embryos have supernumerary ureteric buds, resulting in the development of multiple ureters and multiplex kidneys. These defects are due to increased sensitivity of the Wolffian duct to GDNF/RET signaling, and reducing Gdnf gene dosage correspondingly rescues the Spry1 null phenotype. We conclude that the function of Spry1 is to modulate GDNF/RET signaling in the Wolffian duct, ensuring that kidney induction is restricted to a single site. These results demonstrate the importance of negative feedback regulation of RTK signaling during kidney induction and suggest that failures in feedback control may underlie some human congenital kidney malformations.
Basson
M Albert
MA
Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York, USA. albert.basson@kcl.ac.uk
Akbulut
Simge
S
Watson-Johnson
Judy
J
Simon
Ruth
R
Carroll
Thomas J
TJ
Shakya
Reena
R
Gross
Isabelle
I
Martin
Gail R
GR
Lufkin
Thomas
T
McMahon
Andrew P
AP
Wilson
Patricia D
PD
Costantini
Frank D
FD
Mason
Ivor J
IJ
Licht
Jonathan D
JD
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004627:Embryonic Induction; D005246:Feedback; D005260:Female; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D007668:Kidney / Q000002:abnormalities / Q000196:embryology*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014513:Ureter / Q000002:abnormalities / Q000196:embryology; D014928:Wolffian Ducts / Q000196:embryology
D048868:Adaptor Proteins, Signal Transducing; C495039:GDNF protein, human; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C425468:Spry1 protein, mouse; D004247:DNA; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C494999:Ret protein, mouse