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Hedgehog–TGFβ signalling controls nephrogenesis

Stromal cells are crucial for nephron development through their interaction with nephron progenitor cells (NPCs), but little is known about the pathways involved. Now, Rowan et al. describe a Hedgehog (HH)–GLI–TGFβ axis that controls nephrogenesis.

“In our previous work, we noted a zone of HH activity in the cortical stroma of the embryonic kidney,” explains lead investigator Norman Rosenblum. To investigate this further, the researchers generated mice with stromal-specific deficiency of the HH effector Smoothened (SMO). In embryonic day 15.5 (E15.5) SMO-deficient mice, the renal stromal capsule was disrupted and the number of NPCs was increased. Surprisingly, however, kidney size and nephron number were reduced in SMO-deficient newborn and E18.5 mice, respectively. Thus, stromal HH signalling cell-autonomously controls renal capsule formation and non-cell-autonomously controls NPC number.

Further analysis suggested that defective mesenchymal–epithelial transition in NPCs was responsible for the reduced nephron number in SMO-deficient mice. Moreover, HH signalling exerts these effects on stromal cells and NPCs by controlling the levels of the transcription repressor GLI3R. RNA sequencing of E12.5 kidneys of wild-type and SMO-deficient mice revealed that TGFβ2 was differentially expressed. Inhibition of TGFβ2 in wild-type embryonic kidney explants reduced nephron number, and deletion of TGFβ2 receptor 2 (Tgfbr2) in both stromal cells and NPCs mostly recapitulated the renal defects in SMO deficiency, suggesting that TGFβ2-dependent crosstalk between stromal and cells and NPCs is important for mouse kidney development.

“Our work provides a foundation to study the molecular basis of nephron deficiency, an important cause of childhood and adult-onset kidney disease,” says Rosenblum.

References

Original article

  1. Rowan, C. J. et al. Hedgehog-GLI signaling in Foxd1-positive stromal cells promotes nephrogenesis via TGFβ signaling. Development https://doi.org/10.1242/dev.159947 (2018)

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Correspondence to Grant Otto.

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Otto, G. Hedgehog–TGFβ signalling controls nephrogenesis. Nat Rev Nephrol 14, 598 (2018). https://doi.org/10.1038/s41581-018-0043-1

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