Abstract
The kidney is formed by reciprocal interactions between the nephron progenitor and the ureteric bud, the former of which gives rise to the epithelia of nephrons consisting of glomeruli and renal tubules. The transcription factor PAX2 is essential for this mesenchymal-to-epithelial transition of nephron progenitors, as well as ureteric bud lineage development, in mice. PAX2 mutations in humans cause renal coloboma syndrome. We previously reported the induction of nephron progenitors and three-dimensional nephron structures from human induced pluripotent stem (iPS) cells. Here we generate iPS cells lacking PAX2, and address the role of PAX2 in our in vitro induction protocol. While PAX2-null human nephron progenitors were properly formed, they unexpectedly became epithelialised to form glomeruli and renal tubules. However, the mutant glomerular parietal epithelial cells failed to transit to the squamous morphology, retaining the shape and markers of columnar epithelia. Therefore, PAX2 is dispensable for mesenchymal-to-epithelial transition of nephron progenitors, but is required for morphological development of glomerular parietal epithelial cells, during nephron formation from human iPS cells in vitro.
Highlights
The mammalian kidney, the metanephros, is formed by reciprocally inductive interactions between two precursor tissues, the metanephric mesenchyme and the ureteric bud[1]
We have examined the role of PAX2 in human nephron formation, by utilizing an induction protocol for nephron progenitors from induced pluripotent stem (iPS) cells
By generating homozygous PAX2-null iPS cells, we have demonstrated that PAX2 is dispensable for the formation of nascent nephrons
Summary
The mammalian kidney, the metanephros, is formed by reciprocally inductive interactions between two precursor tissues, the metanephric mesenchyme and the ureteric bud[1]. In the system, isolated metanephric mesenchyme is co-cultured with embryonic spinal cord, and the nephron progenitors in the mesenchyme undergo mesenchymal-to-epithelial transition to form nephron structures, including glomeruli and renal tubules. In this setting, the spinal cord functions as a substitute for the ureteric bud, as both can secrete Wnt ligands and induce differentiation of nephron progenitors[3]. Heterozygous Pax21Neu mice, which harbour a frameshift mutation found in some human patients, exhibit similar phenotypes[15], and genetically-engineered Pax[2] heterozygous mice show kidney hypoplasia[9] These data indicate that the renal coloboma phenotype is caused by PAX2 haploinsufficiency. The precise role and expression patterns of PAX2 in human kidney development are not fully understood, despite the accumulated findings in mice
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