title: Met and the epidermal growth factor receptor act cooperatively to regulate final nephron number and maintain collecting duct morphology.
abstract: 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.
authors.affiliation: Section of Nephrology, Yale University School of Medicine, New Haven, CT 06510, USA. shuta.ishibe@yale.edu
authors.forename: Shuta
authors.initials: S
authors.lastname: Ishibe
authors.forename: Anil
authors.initials: A
authors.lastname: Karihaloo
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Junhui
authors.initials: J
authors.lastname: Zhang
authors.forename: Arnaud
authors.initials: A
authors.lastname: Marlier
authors.forename: Mitchihiro
authors.initials: M
authors.lastname: Mitobe
authors.forename: Akashi
authors.initials: A
authors.lastname: Togawa
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitt
authors.forename: Jan
authors.initials: J
authors.lastname: Czyczk
authors.forename: Michael
authors.initials: M
authors.lastname: Kashgarian
authors.forename: David S
authors.initials: DS
authors.lastname: Geller
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.forename: Lloyd G
authors.initials: LG
authors.lastname: Cantley
mesh_terms: 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
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met