Details

Autor(en) / Beteiligte

• Planas-Paz, Lara
• Orsini, Vanessa
• Boulter, Luke
• Calabrese, Diego
• Pikiolek, Monika
• Nigsch, Florian
• Xie, Yang
• Roma, Guglielmo
• Donovan, Adriana
• Marti, Patricia
• Beckmann, Nicolau
• Dill, Michael T
• Carbone, Walter
• Bergling, Sebastian
• Isken, Andrea
• Mueller, Matthias
• Kinzel, Bernd
• Yang, Yi
• Mao, Xiaohong
• Nicholson, Thomas B
• Zamponi, Raffaella
• Capodieci, Paola
• Valdez, Reginald
• Rivera, Daniel
• Loew, Andreas
• Ukomadu, Chinweike
• Terracciano, Luigi M
• Bouwmeester, Tewis
• Cong, Feng
• Heim, Markus H
• Forbes, Stuart J
• Ruffner, Heinz
• Tchorz, Jan S

Titel

The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size

Ist Teil von

• Nature cell biology, 2016-05, Vol.18 (5), p.467-479

Ort / Verlag

England

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• LGR4/5 receptors and their cognate RSPO ligands potentiate Wnt/β-catenin signalling and promote proliferation and tissue homeostasis in epithelial stem cell compartments. In the liver, metabolic zonation requires a Wnt/β-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/β-catenin-mediated metabolic liver zonation. Liver-specific LGR4/5 loss of function (LOF) or RSPO blockade disrupted hepatic Wnt/β-catenin signalling and zonation. Conversely, pathway activation in ZNRF3/RNF43 LOF mice or with recombinant RSPO1 protein expanded the hepatic Wnt/β-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.