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 witho...

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Published in:	Development (Cambridge) Vol. 136; no. 2; pp. 337 - 345
Main Authors:	Ishibe, Shuta, Karihaloo, Anil, Ma, Hong, Zhang, Junhui, Marlier, Arnaud, Mitobe, Mitchihiro, Togawa, Akashi, Schmitt, Roland, Czyczk, Jan, Kashgarian, Michael, Geller, David S, Thorgeirsson, Snorri S, Cantley, Lloyd G
Format:	Journal Article
Language:	English
Published:	England The Company of Biologists Limited 15-01-2009 Company of Biologists
Subjects:	Animals Base Sequence Development and Disease DNA Primers - genetics Female Kidney - abnormalities Kidney Tubules, Collecting - embryology Kidney Tubules, Collecting - growth & development Kidney Tubules, Collecting - metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Mutant Strains Nephrons - embryology Nephrons - growth & development Nephrons - metabolism Pregnancy Proto-Oncogene Proteins c-met - deficiency Proto-Oncogene Proteins c-met - genetics Proto-Oncogene Proteins c-met - metabolism Receptor, Epidermal Growth Factor - deficiency Receptor, Epidermal Growth Factor - genetics Receptor, Epidermal Growth Factor - metabolism Renal Insufficiency - genetics Renal Insufficiency - pathology RNA, Messenger - genetics RNA, Messenger - metabolism Signal Transduction Ureter - embryology Ureter - metabolism
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This work was supported by an R01 award to L.G.C. (DK65109) and an American Heart Association Fellow-to-Faculty and American Society of Nephrology Gottschalk award to S.I. Deposited in PMC for release after 12 months.
ISSN:	0950-1991 1477-9129
DOI:	10.1242/dev.024463