Axon guidance genes control hepatic artery development

Abstract

Earlier data on liver development demonstrated that morphogenesis of the bile duct, portal mesenchyme and hepatic artery is interdependent, yet how this interdependency is orchestrated remains unknown. Here, using 2D and 3D imaging, we first describe how portal mesenchymal cells organize to form hepatic arteries. Next, we searched for intercellular signalling active during portal area development and found that axon guidance genes are dynamically expressed in developing bile ducts and portal mesenchyme. Using tissue-specific gene inactivation in mice, we show that the Repulsive guidance molecule BMP co-receptor A (Rgma)/Neogenin 1 (Neo1) receptor/ligand pair is dispensable for portal area development, but that deficient Roundabout 2 (Robo2)/Slit2 signalling in the portal mesenchyme causes reduced maturation of the vascular smooth muscle cells that form the tunica media of the hepatic artery. This arterial anomaly does not impact liver function in homeostatic condition but is associated with significant tissular damage following partial hepatectomy. In conclusion, our work identifies new players in development of the liver vasculature in health and liver regeneration.

Inversin‐deficient (inv) mice do not establish a polarized duct system in the liver and pancreas

“…Lower expression of HNF1β in ductal plates of inv mice at P0 might be related to the hepatic artery dilation. Because Gannoun et al (2023) have demonstrated that deficient signaling of roundabout 2 (ROBO2)/SLIT2 in the portal mesenchyme, which may be involved in axon guidance, reduces maturation of the vascular smooth muscle cells that form the tunica media of the hepatic artery, this signaling may play an important role in the hepatic dilation in inv mice. In any event, tissue elements of the intrahepatic bile ducts, hepatic artery, and portal veins can interact with one another to form the portal triad.…”