The tyrosine phosphatase Shp2 acts downstream of GDNF/Ret in branching morphogenesis of the developing mouse kidney.
The tyrosine phosphatase Shp2 acts downstream of various growth factors, hormones or cytokine receptors. Mutations of the Shp2 gene are associated with several human diseases. Here we have ablated Shp2 in the developing kidneys of mice, using the ureteric bud epithelium-specific Hoxb7/Cre. Mutant mice produced a phenotype that is similar to mutations of the genes of the GDNF/Ret receptor system, that is: strongly reduced ureteric bud branching and downregulation of the Ret target genes Etv4 and Etv5. Shp2 mutant embryonic kidneys also displayed reduced cell proliferation at the branch tips and branching defects, which could not be overcome by GDNF in organ culture. We also examined compound mutants of Shp2 and Sprouty1, which is an inhibitor of receptor tyrosine kinase signaling in the kidney. Sprouty1 single mutants produce supernumerary ureteric buds, which branch excessively. Sprouty1 mutants rescued branching deficits in Ret(-/-) and GDNF(-/-) kidneys. Sprouty1; Shp2 double mutants showed no rescue of kidney branching. Our data thus indicate an intricate interplay of Shp2 and Sprouty1 in signaling downstream of receptor tyrosine kinases during kidney development. Apparently, Shp2 mediates not only GDNF/Ret but also signaling by other receptor tyrosine kinases in branching morphogenesis of the embryonic kidney.
Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
Regina
R
Willecke
Julian
J
Heuberger
Katja
K
Grossmann
Odyssé
O
Michos
Kai
K
Schmidt-Ott
Katharina
K
Walentin
Frank
F
Costantini
Walter
W
Birchmeier
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D007668:Kidney / Q000196:embryology* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D044767:Ubiquitin-Protein Ligases; D000070584:Tripartite Motif Proteins
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D044767:Ubiquitin-Protein Ligases; C495040:Gdnf protein, mouse; C093253:Hoxb7 protein, mouse; C425468:Spry1 protein, mouse; C489296:Trim27 protein, mouse; D000070584:Tripartite Motif Proteins