Differential signalling of the WNT and Notch pathways regulates proliferation and differentiation of Lgr5 + cryptbased columnar cells (CBCs) into all cell lineages of the intestine. We have recently shown that high mitochondrial activity in CBCs is key in maintaining stem cell function. Interestingly, while high mitochondrial activity drives CBCs, it is reduced in the adjacent secretory Paneth cells (PCs). This observation implies that during differentiation towards PCs, CBCs undergo a metabolic rewiring involving downregulation of mitochondrial number and activity, through a hitherto unknown mechanism. Here we demonstrate, using intestinal organoids that FoxO transcription factors and Notch signalling functionally interact in determining CBC cell fate. In agreement with the organoid data, combined Foxo1 and 3 deletion in mice increases PC number in the intestine. Importantly, we show that FOXO and Notch signalling converge onto regulation of mitochondrial fission, which in turn provokes stem cell differentiation into the secretory types; Goblet cells and PCs. Finally, mapping intestinal stem cell differentiation based on pseudotime computation of scRNA-seq data further supports the role of FOXO, Notch and mitochondria in determining secretory differentiation. This shows that mitochondria is not only a discriminatory hallmark of CBCs and PCs, but that its status actively determines lineage commitment during differentiation. Together, our work describes a new signalling-metabolic axis in stem cell differentiation and highlights the importance of mitochondria in determining cell fate.
Redox signaling is controlled by the reversible oxidation of cysteine thiols, a post-translational modification triggered by H2O2 acting as a second messenger. However, H2O2 actually reacts poorly with most cysteine thiols and it is not clear how H2O2 discriminates between cysteines to trigger appropriate signaling cascades in the presence of dedicated H2O2 scavengers like peroxiredoxins (PRDXs). It was recently suggested that peroxiredoxins act as peroxidases and facilitate H2O2-dependent oxidation of redox-regulated proteins via disulfide exchange reactions. It is unknown how the peroxiredoxin-based relay model achieves the selective substrate targeting required for adequate cellular signaling. Using a systematic mass-spectrometry-based approach to identify cysteine-dependent interactors of the five human 2-Cys peroxiredoxins, we show that all five human 2-Cys peroxiredoxins can form disulfide-dependent heterodimers with a large set of proteins. Each isoform displays a preference for a subset of disulfide-dependent binding partners, and we explore isoform-specific properties that might underlie this preference. We provide evidence that peroxiredoxin-based redox relays can proceed via two distinct molecular mechanisms. Altogether, our results support the theory that peroxiredoxins could play a role in providing not only reactivity but also selectivity in the transduction of peroxide signals to generate complex cellular signaling responses.
Differential signalling of the WNT and Notch pathways regulates proliferation and differentiation of Lgr5 + cryptbased columnar cells (CBCs) into all cell lineages of the intestine. We have recently shown that high mitochondrial activity in CBCs is key in maintaining stem cell function. Interestingly, while high mitochondrial activity drives CBCs, it is reduced in the adjacent secretory Paneth cells (PCs). This observation implies that during differentiation towards PCs, CBCs undergo a metabolic rewiring involving downregulation of mitochondrial number and activity, through a hitherto unknown mechanism. Here we demonstrate, using intestinal organoids that FoxO transcription factors and Notch signalling functionally interact in determining CBC cell fate. In agreement with the organoid data, combined Foxo1 and 3 deletion in mice increases PC number in the intestine. Importantly, we show that FOXO and Notch signalling converge onto regulation of mitochondrial fission, which in turn provokes stem cell differentiation into the secretory types; Goblet cells and PCs. Finally, mapping intestinal stem cell differentiation based on pseudotime computation of scRNA-seq data further supports the role of FOXO, Notch and mitochondria in determining secretory differentiation. This shows that mitochondria is not only a discriminatory hallmark of CBCs and PCs, but that its status actively determines lineage commitment during differentiation. Together, our work describes a new signalling-metabolic axis in stem cell differentiation and highlights the importance of mitochondria in determining cell fate. 45
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