p63+ ureteric bud tip cells are progenitors of intercalated cells
Samir S. El-Dahr, … , Satrajit Sinha, Zubaida Saifudeen
Samir S. El-Dahr, … , Satrajit Sinha, Zubaida Saifudeen
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e89996. https://doi.org/10.1172/jci.insight.89996.
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Research Article Development Nephrology

p63+ ureteric bud tip cells are progenitors of intercalated cells

Abstract

During renal branching morphogenesis, ureteric bud tip cells (UBTC) serve as the progenitor epithelium for all cell types of the collecting duct. While the transcriptional circuitry of ureteric bud (UB) branching has been intensively studied, the transcriptional control of UBTC differentiation has been difficult to ascertain. This is partly due to limited knowledge of UBTC-specific transcription factors that mark the progenitor state. Here, we identify the transcription factor p63 (also known as TP63), a master regulator of basal stem cells in stratified epithelia, as a specific marker of mouse and human UBTC. Nuclear p63 marks Ret+ UBTC transiently and is silenced by the end of nephrogenesis. Lineage tracing revealed that a subset of UBTC expressing the ΔNp63 isoform (N-terminus truncated p63) is dedicated to generating cortical intercalated cells. Germline targeting of ΔNp63 in mice caused a marked reduction in intercalated cells near the time of birth, indicating that p63 not only marks UBTC, but also is essential for their differentiation. We conclude that the choice of UBTC progenitors to differentiate is determined earlier than previously recognized and that UBTC progenitors are prepatterned and fate restricted. These findings prompt the rethinking of current paradigms of collecting duct differentiation and may have implications for regenerative renal medicine.

Authors

Samir S. El-Dahr, Yuwen Li, Jiao Liu, Elleny Gutierrez, Kathleen S. Hering-Smith, Sabina Signoretti, Jean-Christophe Pignon, Satrajit Sinha, Zubaida Saifudeen

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Figure 1

p63 marks ureteric bud tip progenitors.

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p63 marks ureteric bud tip progenitors. Immunofluorescence (A, B, E–G, I...
Immunofluorescence (A, B, E–G, I, and J) and immunohistochemistry (C, D, and H) using anti-p63 antibody (4A4). (A) At E12, p63 (green) is expressed in skin (inset) but not in the ureteric bud (UB) or UB branches. Pax2 (red) is used as a marker of the nephric lineage. MK, metanephric kidney. (B) At E13.5, p63 (red) is expressed in the UB epithelium but not its branches or tips (arrowhead). E-cadherin (ECAD, green) is used as marker of the UB epithelium. (C and D) E15.5 marks the onset of p63 expression in the UB tip cells (arrowheads). L, liver; g, gonad; k, kidney. (E and F) On E17.5, UB tip–restricted expression of p63 is clearly evident. Arrowheads denote p63+ UB tip cells. (G and H) At P0, p63 marks UB tip cells but not the cap mesenchyme (CM) or UB stalk. (I and J) p63 is silenced after P5. At P10, p63 is not detectable in the maturing collecting ducts but remains present in the pelvic urothelium (n = 3–5 animals per age group). Original magnification, ×4 (C); ×20 (A, B, E, I, and J); ×40 (D, F, H, and all insets); ×60 (G).