AI Article Synopsis
- The study investigates HNF1B, a gene that encodes a transcription factor important for kidney development, and its mutations that lead to kidney malformations.
- Researchers created kidney organoids with HNF1B mutations using CRISPR-Cas9 technology to study the resulting abnormalities at a cellular level.
- Findings revealed that these mutant organoids had deformed tubules and altered gene expression affecting key pathways, contributing to a better understanding of how HNF1B mutations cause kidney disease.
Article Abstract
Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) reprogrammed from a family with HNF1B-associated DKMs. Mutant organoids contained enlarged malformed tubules displaying deregulated cell turnover. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cyclic AMP (cAMP)-mediated dilatation seen in controls. Bulk and single-cell RNA sequencing (scRNA-seq) analyses indicated abnormal Wingless/Integrated (WNT), calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 (GRIK3) was upregulated in malformed mutant nephron tubules and prominent in HNF1B mutant fetal human dysplastic kidney epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule differentiation and morphogenesis illuminating the developmental origin of mutant-HNF1B-causing kidney disease.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297557 | PMC |
| http://dx.doi.org/10.1016/j.stemcr.2024.04.011 | DOI Listing |
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