Abstract: PO1212
Comparative Multiple-Species Analysis of Renal Disease Mutations in HNF1B
Session Information
- Cystic Kidney Disease - I
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Grand, Kelli, Universitat Zurich, Zurich, ZH, Switzerland
- Naert, Thomas, Universitat Zurich, Zurich, ZH, Switzerland
- Rizzo, Ludovica, Universitat Zurich, Zurich, ZH, Switzerland
- Getwan, Maike, Universitat Zurich, Zurich, ZH, Switzerland
- Pichler, Roman, Albert-Ludwigs-Universitat Freiburg Medizinische Fakultat, Freiburg, Baden-Württemberg, Germany
- Lienkamp, Soeren S., Universitat Zurich, Zurich, ZH, Switzerland
Background
Hepatocyte nuclear factor 1-beta (HNF1B) is a transcription factor involved in various stages of nephrogenesis and maintenance of renal tubular functions. Mutations in HNF1B are the most common monogenic causes for developmental renal disease, yet the underlying pathways affected are not fully understood. By comparative analysis in Xenopus and directly reprogrammed mammalian cells (iRECs) we investigated a patient-specific mutation (R295C) associated with cystic-dysplastic kidneys.
Methods
We used HNF1B to form renal-like organoids from Xenopus explants. In parallel, we analyzed how HNF1B R295C affects nephrogenesis in iRECs. Transcriptional changes were comparatively analyzed in two different species. We confirmed HNF1B target candidates in vivo using CRISPR/Cas9 editing of Xenopus embryos.
Results
We show that HNF1B is not only an essential component in direct reprogramming but can also induce ectopic pronephric tissue in Xenopus ectodermal explants. Changes in the transcriptomic profile demonstrated alterations in specific transcriptional modules and identified novel direct and indirect targets of the transcription factor HNF1B, which are linked to signaling pathways associated with renal morphogenesis, cilia and organic anion transport.
Conclusion
In conclusion, the combined use of directly reprogrammed mammalian cells and Xenopus renal organoid experiments allow us to gain a unique perspective into evolutionary conserved mechanisms of renal development and HNF1B associated kidney disease.