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Progenitor translatome changes coordinated by Tsc1 increase perception of Wnt signals to end nephrogenesis

Author

Listed:
  • Alison E. Jarmas

    (University of Cincinnati College of Medicine
    Cincinnati Children’s Hospital Medical Center)

  • Eric W. Brunskill

    (University of Cincinnati College of Medicine
    Cincinnati Children’s Hospital Medical Center)

  • Praneet Chaturvedi

    (University of Cincinnati College of Medicine
    Cincinnati Children’s Hospital Medical Center)

  • Nathan Salomonis

    (Cincinnati Children’s Hospital Medical Center)

  • Raphael Kopan

    (University of Cincinnati College of Medicine
    Cincinnati Children’s Hospital Medical Center)

Abstract

Mammalian nephron endowment is determined by the coordinated cessation of nephrogenesis in independent niches. Here we report that translatome analysis in Tsc1+/− nephron progenitor cells from mice with elevated nephron numbers reveals how differential translation of Wnt antagonists over agonists tips the balance between self-renewal and differentiation. Wnt agonists are poorly translated in young niches, resulting in an environment with low R-spondin and high Fgf20 promoting self-renewal. In older niches we find increased translation of Wnt agonists, including R-spondin and the signalosome-promoting Tmem59, and low Fgf20, promoting differentiation. This suggests that the tipping point for nephron progenitor exit from the niche is controlled by the gradual increase in stability and possibly clustering of Wnt/Fzd complexes in individual cells, enhancing the response to ureteric bud-derived Wnt9b inputs and driving synchronized differentiation. As predicted by these findings, removing one Rspo3 allele in nephron progenitors delays cessation and increases nephron numbers in vivo.

Suggested Citation

  • Alison E. Jarmas & Eric W. Brunskill & Praneet Chaturvedi & Nathan Salomonis & Raphael Kopan, 2021. "Progenitor translatome changes coordinated by Tsc1 increase perception of Wnt signals to end nephrogenesis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26626-9
    DOI: 10.1038/s41467-021-26626-9
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    Cited by:

    1. Naomi Pode-Shakked & Megan Slack & Nambirajan Sundaram & Ruth Schreiber & Kyle W. McCracken & Benjamin Dekel & Michael Helmrath & Raphael Kopan, 2023. "RAAS-deficient organoids indicate delayed angiogenesis as a possible cause for autosomal recessive renal tubular dysgenesis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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