Liver innervation goes viral: mechanisms and functions of neurobiliary cross-talk during development

During embryonic liver development, developing nerves innervate both biliary cells and the vasculature. Biliary cells undergo tubulogenesis to form ducts, but the signals initiating tubulogenesis are unknown.

We discovered that in a human bile duct tubulogenesis disorder, Alagille syndrome (ALGS, caused by JAG1 mutation), and in a mouse model we developed for ALGS, intrahepatic nerves are missing.

In other organ systems, innervation can drive tubulogenesis.We hypothesize that innervation regulates bile duct tubulogenesis.

We will map spatiotemporal liver innervation versus bile duct tubulogenesis using whole mount immunofluorescence of wild type and ALGS mouse embryos and whole livers from embryonic to postnatal stages.

To test the function of nerves in regulating bile duct development, we will interfere with liver innervation in wild type mice using neurotoxins in utero, or neonatal vagatomy, and assess bile duct tubulogenesis.

By adapting our technology NEPTUNE, we will map innervation with barcode labelling, and perform gain and loss of function studies of neurotransmitter pathways in vivo.

Finally, we will re-express Jag1 in neural, biliary or mesenchymal cells to test which of these rescues bile duct morphogenesis in ALGS mice.

Bringing together tools from neuroscience, hepatology and developmental biology, we will determine the neural circuits and mechanisms contributing to liver development.