Abstract: PO0642
Estrogen-Related Receptor Gamma Identified as a Novel Link Between Ciliogenesis and Nephron Development
Session Information
- Development, Stem Cells, and Regenerative Medicine
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 500 Development, Stem Cells, and Regenerative Medicine
Authors
- Weselman, Hannah M., University of Notre Dame Department of Biological Sciences, Notre Dame, Indiana, United States
- Wingert, Rebecca A., University of Notre Dame Department of Biological Sciences, Notre Dame, Indiana, United States
Background
Aberrant formation of cilia, hair-like projections that facilitate mechano- and chemo-sensing, has been linked to developmental disorders, kidney dysfunction, and renal cyst formation. Since prostaglandin signaling has been noted as a key regulator of ciliogenesis, we investigated potential upstream factors that could contribute to both kidney and cilia development. One nuclear receptor, Esrrγ, was of particular interest, as it interacts with known ciliogenic factors and causes renal cysts in mouse knockout models.
Methods
We confirmed that Esrrγ does indeed affect endogenous prostaglandin levels through an ELISA assay of Esrrγ deficiency models. We also assessed the effect of Esrrγ deficiency using whole mount in situ hybridization to characterize changes in distinct nephron cell populations. We used immunohistochemistry to quantify aberrant cilia formation, cell polarity, and cell turnover in the kidney, ear, and node. We utilized qRT-PCR to measure changes in transcription of potential downstream targets, and used overexpression or chemical treatments to rescue with these targets or their products to further support regulatory relationships.
Results
Esrrγ deficient embryos had decreased endogenous PGE2 levels and exhibited nephron composition defects including expanded expression of proximal markers and reduced distal segments. These were likely due to changes in cell fate choice, as no changes in cell death or proliferation were found. The formation of renal cilia was also disrupted, where both cilia length and number of ciliated basal bodies were significantly reduced in ciliated cell populations. Interestingly, Esrrγ was required for ciliogenesis in other tissues as well, as cilia length was also decreased in the node and the ear. These phenotypes were consistent with a disruption of prostaglandin signaling, and we found that expression of the prostaglandin cyclooxygenase enzyme (Cox1) and prostaglandin regulator Pgc1a was reduced in Esrrγ deficient embryos. Treatment with dmPGE2 or Cox1 overexpression was sufficient to rescue renal and cilia defects.
Conclusion
These data position Esrrγ as a novel link between ciliogenesis and nephrogenesis through regulation of prostaglandin signaling, and highlight Esrrγ as a potential new target for future ciliopathic treatments.