The receptor tyrosine kinase regulator Sprouty1 is a target of the tumor suppressor WT1 and important for kidney development.
WT1 encodes a transcription factor involved in kidney development and tumorigenesis. Using representational difference analysis, we identified a new set of WT1 targets, including a homologue of the Drosophila receptor tyrosine kinase regulator, sprouty. Sprouty1 was up-regulated in cell lines expressing wild-type but not mutant WT1. WT1 bound to the endogenous sprouty1 promoter in vivo and directly regulated sprouty1 through an early growth response gene-1 binding site. Expression of Sprouty1 and WT1 overlapped in the developing metanephric mesenchyme, and Sprouty1, like WT1, plays a key role in the early steps of glomerulus formation. Disruption of Sprouty1 expression in embryonic kidney explants by antisense oligonucleotides reduced condensation of the metanephric mesenchyme, leading to a decreased number of glomeruli. In addition, sprouty1 was expressed in the ureteric tree and antisense-treated ureteric trees had cystic lumens. Therefore, sprouty1 represents a physiologically relevant target gene of WT1 during kidney development.
Gross
Isabelle
I
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Morrison
Debra J
DJ
Hyink
Deborah P
DP
Georgas
Kylie
K
English
Milton A
MA
Mericskay
Mathias
M
Hosono
Seiyu
S
Sassoon
David
D
Wilson
Patricia D
PD
Little
Melissa
M
Licht
Jonathan D
JD
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D015152:Blotting, Northern; D002843:Chromatin / Q000378:metabolism; D003001:Cloning, Molecular; D004330:Drosophila; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D007150:Immunohistochemistry; D007668:Kidney / Q000196:embryology* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000196:embryology; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008957:Models, Genetic; D041681:NIH 3T3 Cells; D009841:Oligonucleotides / Q000737:chemistry; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism* / Q000502:physiology*; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D025721:WT1 Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; D008565:Membrane Proteins; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D010750:Phosphoproteins; C425468:Spry1 protein, mouse; D025721:WT1 Proteins