A morphogenetic EphB/EphrinB code controls hepatopancreatic duct formation

Letizia Satriano,Jesper B Andersen,Ronja L S Heyne,Elke A Ober,M Ilcim Thestrup,Sara Caviglia,Wolfgang Hofmeister,David G Wilkinson,Racha Ahmad,Jordi Cayuso

doi:10.1038/s41467-019-13149-7

Abstract

The hepatopancreatic ductal (HPD) system connects the intrahepatic and intrapancreatic ducts to the intestine and ensures the afferent transport of the bile and pancreatic enzymes. Yet the molecular and cellular mechanisms controlling their differentiation and morphogenesis into a functional ductal system are poorly understood. Here, we characterize HPD system morphogenesis by high-resolution microscopy in zebrafish. The HPD system differentiates from a rod of unpolarized cells into mature ducts by de novo lumen formation in a dynamic multi-step process. The remodeling step from multiple nascent lumina into a single lumen requires active cell intercalation and myosin contractility. We identify key functions for EphB/EphrinB signaling in this dynamic remodeling step. Two EphrinB ligands, EphrinB1 and EphrinB2a, and two EphB receptors, EphB3b and EphB4a, control HPD morphogenesis by remodeling individual ductal compartments, and thereby coordinate the morphogenesis of this multi-compartment ductal system.

Highlights

The hepatopancreatic ductal (HPD) system connects the intrahepatic and intrapancreatic ducts to the intestine and ensures the afferent transport of the bile and pancreatic enzymes
At 52 hpf, the GB primordium is detectable by dense group of atypical protein kinase C λ (aPKC) foci and its round morphology at the distal end of the common bile duct (CBD) (Fig. 1c), which later will connect to the extrahepatic duct (EHD)-CBD lumen via the cystic duct (CD)
We show that the HPD system differentiates by a dynamic morphogenetic process, in which a mature tube forms by a multi-step cord-hollowing mechanism

Summary

Introduction

The hepatopancreatic ductal (HPD) system connects the intrahepatic and intrapancreatic ducts to the intestine and ensures the afferent transport of the bile and pancreatic enzymes. The HPD system is essential for food processing and uptake of nutrients, as it transports the bile produced in the liver, as well as pancreatic enzymes and electrolytes to the intestine, but little is known about how the HPD develops It is a multi-component system consisting of the extrahepatic duct (EHD), cystic duct (CD), common bile duct (CBD) and extrapancreatic duct (EPD; Fig. 1f)[1]. HPD progenitors arise from an endodermal cell population located between the liver and pancreas anlagen In mouse, this population co-expresses transcription factors Sox[17] and Pdx[1], with Sox[17] being essential for EHB duct formation[8]. Due to limited sample accessibility and developmental stages, current understanding is incomplete and an in-depth analysis is necessary

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Conclusion