Kidney Development in the Absence of Gdnf and Spry1 Requires Fgf10

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Kidney Development in the Absence of Gdnf and Spry1 Requires Fgf10

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dc.contributor.author Michos, Odyssé
dc.contributor.author Cebrian, Cristina
dc.contributor.author Hyink, Deborah
dc.contributor.author Grieshammer, Uta
dc.contributor.author D'Agati, Vivette
dc.contributor.author Licht, Jonathan D.
dc.contributor.author Martin, Gail R.
dc.contributor.author Costantini, Frank
dc.contributor.author Williams, Linda
dc.date.accessioned 2012-02-19T23:19:47Z
dc.date.issued 2010
dc.identifier.citation Michos, Odyssé, Cristina Cebrian, Deborah Hyink, Uta Grieshammer, Linda Williams, Vivette D'Agati, Jonathan D. Licht, Gail R. Martin, and Frank Costantini. 2010. Kidney development in the absence of Gdnf and Spry1 requires Fgf10. PLoS Genetics 6(1): e1000809. en_US
dc.identifier.issn 1553-7390 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:8191175
dc.description.abstract GDNF signaling through the Ret receptor tyrosine kinase (RTK) is required for ureteric bud (UB) branching morphogenesis during kidney development in mice and humans. Furthermore, many other mutant genes that cause renal agenesis exert their effects via the GDNF/RET pathway. Therefore, RET signaling is believed to play a central role in renal organogenesis. Here, we re-examine the extent to which the functions of Gdnf and Ret are unique, by seeking conditions in which a kidney can develop in their absence. We find that in the absence of the negative regulator Spry1, Gdnf, and Ret are no longer required for extensive kidney development. Gdnf−/−;Spry1−/− or Ret−/−;Spry1−/− double mutants develop large kidneys with normal ureters, highly branched collecting ducts, extensive nephrogenesis, and normal histoarchitecture. However, despite extensive branching, the UB displays alterations in branch spacing, angle, and frequency. UB branching in the absence of Gdnf and Spry1 requires Fgf10 (which normally plays a minor role), as removal of even one copy of Fgf10 in Gdnf−/−;Spry1−/− mutants causes a complete failure of ureter and kidney development. In contrast to Gdnf or Ret mutations, renal agenesis caused by concomitant lack of the transcription factors ETV4 and ETV5 is not rescued by removing Spry1, consistent with their role downstream of both RET and FGFRs. This shows that, for many aspects of renal development, the balance between positive signaling by RTKs and negative regulation of this signaling by SPRY1 is more critical than the specific role of GDNF. Other signals, including FGF10, can perform many of the functions of GDNF, when SPRY1 is absent. But GDNF/RET signaling has an apparently unique function in determining normal branching pattern. In contrast to GDNF or FGF10, Etv4 and Etv5 represent a critical node in the RTK signaling network that cannot by bypassed by reducing the negative regulation of upstream signals. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pgen.1000809 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797609/pdf/ en_US
dash.license LAA
dc.title Kidney Development in the Absence of Gdnf and Spry1 Requires Fgf10 en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS Genetics en_US
dash.depositing.author Williams, Linda
dc.date.available 2012-02-19T23:19:47Z
dash.affiliation.other HMS^Psychiatry-Massachusetts General Hospital en_US

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