Defining the Role of Hedgehog-GLI Signaling in the Renal Cortical Stroma

In the mammalian kidney, Foxd1-positive stroma interacts with nephron progenitors to control nephrogenesis. Here we establish a non-cell autonomous role for stromal-Hedgehog (HH) signaling in controlling nephron progenitor differentiation and self-renewal. Stromal-specific inhibition of Smo, the HH signal transducer, results in an expanded domain of nephron progenitors and an increase in cell proliferation. Smo-deficient kidneys exhibit a specific inhibition in the formation of renal vesicles, a nephron intermediary structure. In parallel, Lim1 expression, a requirement for the progression of nephrogenesis, is decreased. HH signaling mediates its downstream effects by promoting GLI transcriptional activator levels while inhibiting GLI3 processing to a transcriptional repressor (GLI3R). Deletion of Gli3 in Smo-deficient mice normalized kidney volume and nephron number. Stromal-specific expression of Gli3R (obligate and conditional) phenocopies Smo-deficient mice, thus further supporting a deleterious role for GLI3R in the stroma. Together, our results provide novel insight into HH-GLI dependent interactions within the nephrogenic niche.M.Sc.2018-01-05 00:00:0