期刊
NATURE CELL BIOLOGY
卷 18, 期 5, 页码 467-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3337
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资金
- Leverhulme Trust [ECF-2012-262]
- SNF grant [310030B_147089]
- MRC Centre Grant
- UKRMP Niche hub grant [MR/K026666/1]
- Novartis Institutes for BioMedical Research Postdoctoral Program
- Medical Research Council [MR/K026666/1] Funding Source: researchfish
- MRC [MR/K026666/1] Funding Source: UKRI
LGR4/5 receptors and their cognate RSPO ligands potentiate Wnt/beta-catenin signalling and promote proliferation and tissue homeostasis in epithelial stem cell compartments. In the liver, metabolic zonation requires a Wnt/beta-catenin signalling gradient, but the instructive mechanism controlling its spatiotemporal regulation is not known. We have now identified the RSPO-LGR4/5-ZNRF3/RNF43 module as a master regulator of Wnt/beta-catenin-mediated metabolic liver zonation. Liver-specific LGR4/5 loss of function (LOF) or RSPO blockade disrupted hepatic Wnt/beta-catenin signalling and zonation. Conversely, pathway activation in ZNRF3/RNF43 LOF mice or with recombinant RSPO1 protein expanded the hepatic Wnt/beta-catenin signalling gradient in a reversible and LGR4/5-dependent manner. Recombinant RSPO1 protein increased liver size and improved liver regeneration, whereas LGR4/5 LOF caused the opposite effects, resulting in hypoplastic livers. Furthermore, we show that LGR4(+) hepatocytes throughout the lobule contribute to liver homeostasis without zonal dominance. Taken together, our results indicate that the RSPO-LGR4/5-ZNRF3/RNF43 module controls metabolic liver zonation and is a hepatic growth/size rheostat during development, homeostasis and regeneration.
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