The mechanisms by which stem cell (SC) quiescence is regulated to allow normal regeneration are poorly understood. Here, we show that the mesenchymal niche of the hair follicle, the dermal papilla (DP), governs the properties of quiescent SCs in the bulge despite its relatively distant location. The DP induces regeneration by downregulating bulge-dependent inhibitory effects that restrain the intrinsic proliferation features of primed progenitors. Once regeneration initiates, the DP orchestrates Shh expression in primed-progenitor descendants by an autoregulatory circuit to restrict Shh expression to the DP vicinity and to confine Shh levels to act only on nearby cells. As the DP moves away from the bulge, quiescent SCs are exposed to Shh transiently. This ensures a short period of quiescent SC activation required for normal regeneration. Furthermore, our findings show that Shh signaling in the DP fine-tunes Wnt signaling activity and reveal the importance of signaling cross talk in coordinating regeneration pace.

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Among the earliest protein products of most cellular genes are those synthesized during the pioneer round of translation (PRT), a key step in nonsense‐mediated mRNA decay (NMD) that allows scanning of new transcripts for the presence of a premature termination codon (PTC). It has been demonstrated that at least some PRT degradation products can be targeted to major histocompatibility (MHC)‐I presentation. To gain new insight into this putative PRT‐to‐MHC‐I route, we have assembled 2 pairs of reporter genes so that the 2 genes in each pair encode an identical fusion protein between a model antigenic peptide and enhanced green fluorescent protein (EGFP), one of which harbors a PTC. We expressed these genes in different mouse and human cell lines and confirmed enhanced NMD activity for the PTC(+) gene in each pair by monitoring the effect of cycloheximide on the level of the respective mRNA. We then exploited several strategies for establishing the ratio between level of peptide presentation and total amount of protein product. We consistently observed significantly higher ratios for the PTC(+) mRNAs compared with the PTC(−) ones, pointing to correlation between the turnover of otherwise identical proteins and the fate of their template mRNA. Using confocal microscopy, we showed a clear link between NMD, the presence of misfolded EGFP polypeptides, and enhanced MHC‐I peptide presentation. Altogether, these findings imply that identical full‐length gene products differing only in 3′ noncoding sequences can be differentially degraded and targeted to the MHC‐I presentation pathway, suggesting a more general role for the PRT in establishing the MHC‐I peptidome.—Weinstein‐Marom, H., Hendel, L., Laron, E. A., Sharabi‐Nov, A., Margalit, A., Gross, G. MHC‐I presentation of peptides derived from intact protein products of the pioneer round of translation. FASEB J. 33, 11458–11468 (2019). http://www.fasebj.org