Age-Dependent Changes in the Progenitor Translatome Coordinated in part by Tsc1 Increase Perception of Signaling Inputs to End Nephrogenesis

Eric Brunskill, Alison Jarmas, Praneet Chaturvedi, Raphael Kopan

Like Comment

Received Date: 6th April 20

Mammalian nephron endowment is determined by the coordinated cessation of nephrogenesis in independent niches. Translatome analysis in Tsc1+/– with high nephron numbers reveled differential translation of Wnt antagonists over agonists, expanding a transitional (Six2+, Cited1+, Wnt4+) state and delaying the tipping point. Moreover, in all strains tested Wnt agonists are poorly translated in young niches, resulting in high Fgf20 levels low and R-spondin levels and promoting  a self-renewal environment. By contrast, we find increased cellular translation of Wnt agonists, including the signalosome-promoting Tmem59, in older niches that are low in Fgf20. This suggests a hypothesis that the tipping point for nephron progenitor exit from the niche is controlled by the gradual increase in stability and clustering of Wnt/Fzd complexes in individual cells, enhancing the response to ureteric bud-derived Wnt9b inputs and driving differentiation. As predicted by these findings, removing one Rspo3 allele in nephron progenitors or global deletion of Tmem59 increased nephron numbers in vivo.

Read in full at bioRxiv.

This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature