Abstract
Mesenchymal nephron progenitors (mNPs) give rise to all nephron tubules in the mammalian kidney. Since premature depletion of these cells leads to low nephron numbers, high blood pressure, and various renal diseases, it is critical that we understand how mNPs are maintained. While Fgf, Bmp, and Wnt signaling pathways are known to be required for the maintenance of these cells, it is unclear if any other signaling pathways also play roles. In this report, we explored the role of Hedgehog signaling in mNPs. We found that loss of either Shh in the collecting duct or Smo from the nephron lineage resulted in premature depletion of mNPs. Transcriptional profiling of mNPs with different Smo dosages suggested that Hedgehog signaling inhibited Notch signaling and upregulated the expression of Fox transcription factors such as Foxc1 and Foxp4. Consistent with these observations, we found that ectopic expression of Jag1 caused the premature depletion of mNPs as seen in the Smo mutant kidney. We also found that Foxc1 was capable of binding to mitotic condensed chromatin, a feature of a mitotic bookmarking factor. Our study demonstrates a previously unappreciated role of Hedgehog signaling in preventing premature depletion of mNPs by repressing Notch signaling and likely by activating the expression of Fox factors.