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