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
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.
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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 It has not been peer reviewed but is currently under consideration at Nature Communications.