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Guided Differentiation of Mature Kidney Podocytes from Human Induced Pluripotent Stem Cells Under Chemically Defined Conditions
Published on: July 2, 2020
The podocyte-specific inactivation of Lmx1b, Ldb1 and E2a yields new insight into a transcriptional network in
Hani Suleiman1, Daniel Heudobler, Anne-Sarah Raschta
1University of Regensburg, Institute for Molecular and Cellular Anatomy, Universitätsstr. 31, 93053 Regensburg, and Division of Nephrology and Immunology, University Hospital, RWTH, Aachen, Germany.
Abstract:
Patients with nail-patella syndrome, which among other symptoms also includes podocyte-associated renal failure, suffer from mutations in the LMX1B gene. The disease severity among patients is quite variable and has given rise to speculations on the presence of modifier genes. Promising candidates for modifier proteins are the proteins interacting with LMX1B, such as LDB1 and E47. Since human kidney samples from patients are difficult to obtain, conventional Lmx1b knock-out mice have been extremely valuable to study the role of Lmx1b in podocyte differentiation. In contrast to findings in these mice, however, in which a downregulation of the Col4a3, Col4a4 and Nphs2 genes has been described, no such changes have been detected in kidney biopsies from patients. We now report on our results on the characterization of constitutive podocyte-specific Lmx1b, Ldb1 and E2a knock-out mice. Constitutive podocyte-specific Lmx1b knock-out mice survive for approximately 2 weeks after birth and do not present with a downregulation of the Col4a3, Col4a4 and Nphs2 genes, therefore they mimic the human disease more closely. The podocyte-specific Ldb1 knock-out mice survive longer, but then also succumb to renal failure, whereas the E2a knock-out mice show no renal symptoms for at least 6 months after birth. We conclude that LDB1, but not E2A is a promising candidate as a modifier gene in patients with nail-patella syndrome.
Insights
Mutations in the LMX1B gene cause nail-patella syndrome. LDB1, but not E2A, shows potential as a modifier gene in patients, as demonstrated in new mouse models that better mimic human disease progression.
Area of Science:
- Genetics
- Nephrology
- Developmental Biology
Background:
- Nail-patella syndrome (NPS) is a genetic disorder characterized by mutations in the LMX1B gene, leading to podocyte-associated renal failure.
- Disease severity in NPS patients varies, suggesting the influence of modifier genes.
- Previous Lmx1b knockout mouse models did not fully replicate human NPS kidney pathology.
Purpose of the Study:
- To characterize podocyte-specific knockout mouse models for Lmx1b, Ldb1, and E2a to investigate their roles in NPS pathogenesis.
- To identify potential modifier genes that influence the variable disease severity observed in nail-patella syndrome patients.
Main Methods:
- Generation and analysis of constitutive podocyte-specific knockout mice for Lmx1b, Ldb1, and E2a.
- Assessment of survival rates and renal phenotypes, including gene expression analysis (Col4a3, Col4a4, Nphs2).
- Comparison of mouse model phenotypes with human kidney biopsy data from NPS patients.
Main Results:
- Podocyte-specific Lmx1b knockout mice survived ~2 weeks and did not show downregulation of Col4a3, Col4a4, and Nphs2, closely mimicking human disease.
- Podocyte-specific Ldb1 knockout mice developed renal failure, indicating LDB1's role.
- Podocyte-specific E2a knockout mice showed no renal symptoms up to 6 months, suggesting E2A is not a significant modifier.
Conclusions:
- LDB1 is a promising candidate modifier gene for nail-patella syndrome.
- E2A is unlikely to be a significant modifier gene in nail-patella syndrome.
- Podocyte-specific knockout models provide valuable insights into NPS pathogenesis and modifier gene identification.
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