Hnf4ais required for the development of Cdh6-expressing progenitors into proximal tubules in the mouse kidney
Abstract
Background
Hnf4a is a major regulator of renal proximal tubule (PT) development. In humans, a mutation inHNF4Ais associated with Fanconi renotubular syndrome (FRTS), which is caused by defective PT functions. In mice, mosaic deletion ofHnf4ain the developing kidney causes a paucity of PT cells, leading to FRTS-like symptoms. The molecular mechanisms underlying the role of Hnf4a in PT development remain unclear.
Methods
We generated a newHnf4amutant mouse model employingOsr2Cre,which effectively deletesHnf4ain developing nephrons. We characterized the mutant phenotype by immunofluorescence analysis. We performed lineage analysis to test if Cdh6-expressing cells are PT progenitors. We also performed genome-wide mapping of Hnf4a binding sites and differential gene analysis ofHnf4amutant kidneys to identify direct target genes of Hnf4a.
Results
Deletion ofHnf4awithOsr2Creled to the complete loss of mature PT cells, causing lethality in theHnf4amutant mice. We found that Cdh6high, LTLlowcells serve as PT progenitors and that they show higher proliferation than Cdh6low, LTLhighdifferentiated PT cells. We also found that Hnf4a is required for PT progenitors to develop into differentiated PT cells. Our genomic analyses revealed that Hnf4a directly regulates the expression of genes involved in transmembrane transport and metabolism.
Conclusions
Our findings show that Hnf4a promotes the development of PT progenitors into differentiated PT cells by regulating the expression of genes associated with reabsorption, the major function of PT cells.
Significance
Proximal tubule cells are the most abundant cell type in the mammalian kidney and they perform the bulk of the renal reabsorption function. Despite their importance in kidney function, the molecular mechanisms of proximal tubule development and maturation are not well understood. Here we find that, in the developing mouse kidney, Cdh6high, LTLlowcells act as proximal tubule progenitors and that Hnf4a is required for these cells to further develop into proximal tubules. Our genomic analyses show that Hnf4a directly regulate the expression of genes required for reabsorption such as transmembrane transport genes and metabolism genes. This study advances our understanding of how kidney proximal tubule cells form during development.
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