Zonation of Morphogens in the adult liver – Crosstalk between Hh and Wnt/β-Catenin signaling

Background:

Metabolic pathways in the liver are strongly zonated, partially caused by adapting to changing contents of nutrients and oxygen within the porto-central axis. Recently the impact of morphogens like Hedgehog (Hh) and Wnt/β-Catenin on liver zonation and metabolism has sparked increasing interest. Long time the interplay between pericentral located Wnt and its periportal located zonation-keeper APC were thought to be exclusively responsible for morphogenic controlled liver zonation. More recently our group could demonstrate that inhibition of the Hh-pathway leads to increased liver lipid accumulation which resembles a disease pattern of non-alcoholic liver disease. As it is known for Wnt/β-Catenin, Hh signaling likely influences other metabolic activities. For a better understanding of metabolic liver zonation under morphogenic control we aimed at demonstrating the mutual impact and zonal distribution of Hh and Wnt signaling.

Methods:

Different hepatocyte-specific transgenic mice models were breeded. These mice, allowing investigating the mutual impact of Hh and Wnt/β-Catenin signaling by activation or inhibition of Wnt and Hh. Hh activation was aimed by Ptch1 deletion, leading to loss of Smo repression. Hh inhibition was achieved by Smo knockout. Wnt/β-Catenin signaling was enhanced by targeting APC. To depict the porto-central distribution of different pathway markers liver slices were stained by immunohistochemistry (IHC). Based on immunohistochemistry we established a zonation model using the TiQuant software.

Results:

Our results point towards a crosstalk between Wnt and Hh in the liver parenchyma. By IHC we could show that upregulation of Wnt/β-Catenin signaling is associated with a pericentral expansion of Indian Hh, Axin2 and Fzd4, Furthermore we could demonstrate that Fzd2 and its potential ligand Wnt5a are most likely periportal expressed and are repressed towards the portal vein by upregulation of Wnt/β-Catenin signaling.

Conclusion:

Our results indicate an intensive interplay between Wnt and Hh. In addition our quantification model pinpoints that Wnt signaling most likely is not generally restricted to pericentral action. Weather periportal Fzd2/Wnt5a signaling contributes to morphogenic liver zonation and how the crosstalk between Wnt and Hh can impact metabolic zonation must be elucidated in additional experiments.