Journal
DEVELOPMENT
Volume 138, Issue 7, Pages 1275-1280Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.062158
Keywords
Fibroblast growth factor receptor 2; Frs2 alpha; Ureteric epithelium; Mouse
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK070030]
- National Institutes of Health [P50 AR054086]
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Mice with conditional deletion of fibroblast growth factor receptor 2 (Fgfr2) in the ureteric bud using a Hoxb7cre line (Fgfr2(UB-/-)) develop severe ureteric branching defects; however, ureteric deletion of fibroblast growth factor receptor substrate 2 alpha (Frs2 alpha), a key docking protein that transmits fibroblast growth factor receptor intracellular signaling (Frs2 alpha(UB-/-)) leads to mild ureteric defects. Mice with point mutations in the Frs2 alpha binding site of Fgfr2 (Fgfr2(LR/LR)) have normal kidneys. The aim of this study was to determine the relationship between Fgfr2 and Frs2 alpha in the ureteric lineage. Mice with ureteric deletion of both Fgfr2 and Frs2 alpha (Fgfr2/Frs2 alpha(UB-/)) were compared with Frs2 alpha(UB-/-) and Fgfr2(UB-/-) mice. To avoid potential rescue of Fgfr1 forming heterodimers with Fgfr2(LR) alleles to recruit Frs2 alpha, compound mutant mice were generated with ureteric deletion of Fgfr1 and with Fgfr2(LR/LR) point mutations (Fgfr1(UB-/-)Fgfr2(LR/LR)). At E13.5, three-dimensional reconstructions and histological assessment showed that, whereas Fgfr2(UB-/-) kidneys had more severe ureteric branching defects than Frs2 alpha(UB-/-), Fgfr2(UB-/-) kidneys were indistinguishable from Fgfr2/Frs2 alpha(UB-/-). At later stages, however, Fgfr2/Frs2 alpha(UB-/-) kidneys were more severely affected than either Fgfr2(UB-/-) or Frs2 alpha(UB-/-) kidneys. Taken together, although Fgfr2 and Frs2 alpha have crucial roles in the ureteric lineage, they appear to act separately and additively.
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