1. Stage specific requirement of Gfrα1 in the ureteric epithelium during kidney development.
- Author
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Keefe Davis T, Hoshi M, and Jain S
- Subjects
- Animals, Cell Proliferation, Congenital Abnormalities metabolism, Embryo, Mammalian, Epithelial Cells cytology, Extracellular Signal-Regulated MAP Kinases genetics, Extracellular Signal-Regulated MAP Kinases metabolism, Female, Gene Expression Regulation, Developmental, Glial Cell Line-Derived Neurotrophic Factor genetics, Glial Cell Line-Derived Neurotrophic Factor metabolism, Glial Cell Line-Derived Neurotrophic Factor Receptors metabolism, Kidney cytology, Kidney growth & development, Kidney Diseases genetics, Kidney Diseases metabolism, Male, Mesoderm cytology, Mesoderm growth & development, Mice, Mice, Transgenic, Organogenesis genetics, Proto-Oncogene Proteins c-ret genetics, Proto-Oncogene Proteins c-ret metabolism, Signal Transduction, Tissue Culture Techniques, Ureter cytology, Ureter growth & development, Wolffian Ducts cytology, Wolffian Ducts growth & development, Wolffian Ducts metabolism, Congenital Abnormalities genetics, Epithelial Cells metabolism, Glial Cell Line-Derived Neurotrophic Factor Receptors genetics, Kidney abnormalities, Kidney metabolism, Kidney Diseases congenital, Mesoderm metabolism, Ureter metabolism
- Abstract
Glial cell line-derived neurotrophic factor (GDNF) binds a coreceptor GDNF family receptor α1 (GFRα1) and forms a signaling complex with the receptor tyrosine kinase RET. GDNF-GFRα1-RET signaling activates cellular pathways that are required for normal induction of the ureteric bud (UB) from the Wolffian duct (WD). Failure of UB formation results in bilateral renal agenesis and perinatal lethality. Gfrα1 is expressed in both the epithelial and mesenchymal compartments of the developing kidney while Ret expression is specific to the epithelium. The biological importance of Gfrα1's wider tissue expression and its role in later kidney development are unclear. We discovered that conditional loss of Gfrα1 in the WD epithelium prior to UB branching is sufficient to cause renal agenesis. This finding indicates that Gfrα1 expressed in the nonepithelial structures cannot compensate for this loss. To determine Gfrα1's role in branching morphogenesis after UB induction we used an inducible Gfrα1-specific Cre-deletor strain and deleted Gfrα1 from the majority of UB tip cells post UB induction in vivo and in explant kidney cultures. We report that Gfrα1 excision from the epithelia compartment after UB induction caused a modest reduction in branching morphogenesis. The loss of Gfrα1 from UB-tip cells resulted in reduced cell proliferation and decreased activated ERK (pERK). Further, cells without Gfrα1 expression are able to populate the branching UB tips. These findings delineate previously unclear biological roles of Gfrα1 in the urinary tract and demonstrate its cell-type and stage-specific requirements in kidney development., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2013
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