# Hedgehog gene regulatory networks in the mammalian kidney

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $505,892

## Abstract

Project Summary/Abstract
Mesenchymal nephron progenitor cells (MNPs) give rise to all nephron tubules in the mammalian kidney.
Premature depletion of these cells leads to low nephron numbers, increasing the risk of high blood pressure
and various renal diseases. In order to intervene in premature depletion of MNPs, we must better understand
how the MNP population is maintained during development. To date, the processes required for the
maintenance of MNPs in vivo are poorly understood. Our preliminary data suggest that Hedgehog signaling
plays important roles in MNP maintenance. Hedgehog signaling regulates numerous developmental
processes. Upon binding of Hedgehog to Patched, Smoothened (Smo) is relieved from Patched-mediated
inhibition, initiating the signaling cascade. To test the potential role of Hedgehog signaling in MNPs, we
generated Smo mutant kidneys with Six2Cre and found that MNPs lacking Smo were prematurely depleted
during development, resulting in a 50% reduction in nephron number. Our transcriptional profiling data from
Smo loss- and gain-of-function mutant MNPs show a linear correlation between Ptch1 expression and Smo
dosage, suggesting that MNPs do respond to Hedgehog signaling. Our data show that Fox transcription factors
are downstream targets of Hedgehog signaling in MNPs and that loss of Hedgehog signaling results in the
activation of Notch signaling, a major differentiation signal for MNPs. Based on our findings, we hypothesize
that ligand-dependent Hedgehog signaling maintains MNPs by repressing Notch signal and activating Fox
genes. We propose to (1) perform genetic analyses to determine if Hedgehog signaling increases self-renewal
of MNPs and nephron endowment, (2) test if genetic attenuation or pharmacological inhibition of Notch
signaling rescues premature depletion of Smo mutant MNPs, and (3) test if loss of Fox transcription factors
results in premature depletion of MNPs and lower nephron numbers. Successful completion of these aims will
(1) provide novel insights into how Hedgehog signaling impacts nephron endowment, (2) identify direct target
genes operating downstream of Hedgehog signaling in MNPs, (3) determine if Fox transcription factors play
key roles in nephrogenesis, and (4) improve in vitro renal organoid cultures.

## Key facts

- **NIH application ID:** 10344254
- **Project number:** 1R01DK131052-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Joo-Seop Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $505,892
- **Award type:** 1
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10344254

## Citation

> US National Institutes of Health, RePORTER application 10344254, Hedgehog gene regulatory networks in the mammalian kidney (1R01DK131052-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10344254. Licensed CC0.

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