Stage specific requirement of Gfr alpha 1 in the ureteric epithelium during kidney development

摘要

Glial cell line-derived neurotrophic factor (GDNF) binds a coreceptor GDNF family receptor alpha 1 (GFR alpha 1) and forms a signaling complex with the receptor tyrosine kinase RET. GDNF-GFR alpha 1-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. Gfr alpha 1 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 Gfr alpha 1's wider tissue expression and its role in later kidney development are unclear. We discovered that conditional loss of Gfr alpha 1 in the WD epithelium prior to UB branching is sufficient to cause renal agenesis. This finding indicates that Gfr alpha 1 expressed in the nonepithelial structures cannot compensate for this loss. To determine Gfr alpha 1's role in branching morphogenesis after UB induction we used an inducible Gfr alpha 1-specific Cre-deletor strain and deleted Gfr alpha 1 from the majority of UB tip cells post UB induction in vivo and in explant kidney cultures. We report that Gfr alpha 1 excision from the epithelia compartment after UB induction caused a modest reduction in branching morphogenesis. The loss of Gfr alpha 1 from UB-tip cells resulted in reduced cell proliferation and decreased activated ERK (pERK). Further, cells without Gfr alpha 1 expression are able to populate the branching UB tips. These findings delineate previously unclear biological roles of Gfr alpha 1 in the urinary tract and demonstrate its cell-type and stage-specific requirements in kidney development.