Met and the epidermal growth factor receptor act cooperatively to regulate final nephron number and maintain collecting duct morphology.
Ureteric bud (UB) branching during kidney development determines the final number of nephrons. Although hepatocyte growth factor and its receptor Met have been shown to stimulate branching morphogenesis in explanted embryonic kidneys, loss of Met expression is lethal during early embryogenesis without obvious kidney abnormalities. Met(fl/fl);HoxB7-Cre mice, which lack Met expression selectively in the UB, were generated and found to have a reduction in final nephron number. These mice have increased Egf receptor expression in both the embryonic and adult kidney, and exogenous Egf can partially rescue the branching defect seen in kidney explants. Met(fl/fl);HoxB7-Cre;wa-2/wa-2 mice, which lack normal Egfr and Met signaling, exhibit small kidneys with a marked decrease in UB branching at E14.5 as well as a reduction in final glomerular number. These mice developed progressive interstitial fibrosis surrounding collecting ducts with kidney failure and death by 3-4 weeks of age. Thus, in support of previous in vitro findings, Met and the Egf receptor can act cooperatively to regulate UB branching and mediate maintenance of the normal adult collecting duct.
Ishibe
Shuta
S
Section of Nephrology, Yale University School of Medicine, New Haven, CT 06510, USA. shuta.ishibe@yale.edu
Karihaloo
Anil
A
Ma
Hong
H
Zhang
Junhui
J
Marlier
Arnaud
A
Mitobe
Mitchihiro
M
Togawa
Akashi
A
Schmitt
Roland
R
Czyczk
Jan
J
Kashgarian
Michael
M
Geller
David S
DS
Thorgeirsson
Snorri S
SS
Cantley
Lloyd G
LG
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D066246:ErbB Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007668:Kidney / Q000002:abnormalities; D007685:Kidney Tubules, Collecting / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009399:Nephrons / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism; D011247:Pregnancy; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051437:Renal Insufficiency / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D014513:Ureter / Q000196:embryology / Q000378:metabolism
D017931:DNA Primers; D012333:RNA, Messenger; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met