EphrinB1/EphB3b Coordinate Bidirectional Epithelial-Mesenchymal Interactions Controlling Liver Morphogenesis and Laterality

Abstract

SummaryPositioning organs in the body often requires the movement of multiple tissues, yet the molecular and cellular mechanisms coordinating such movements are largely unknown. Here, we show that bidirectional signaling between EphrinB1 and EphB3b coordinates the movements of the hepatic endoderm and adjacent lateral plate mesoderm (LPM), resulting in asymmetric positioning of the zebrafish liver. EphrinB1 in hepatoblasts regulates directional migration and mediates interactions with the LPM, where EphB3b controls polarity and movement of the LPM. EphB3b in the LPM concomitantly repels hepatoblasts to move leftward into the liver bud. Cellular protrusions controlled by Eph/Ephrin signaling mediate hepatoblast motility and long-distance cell-cell contacts with the LPM beyond immediate tissue interfaces. Mechanistically, intracellular EphrinB1 domains mediate EphB3b-independent hepatoblast extension formation, while EpB3b interactions cause their destabilization. We propose that bidirectional short- and long-distance cell interactions between epithelial and mesenchyme-like tissues coordinate liver bud formation and laterality via cell repulsion.

An Ephrin-Eph Tug and Push in Left-Right Organ Placement

“…Reporting in Developmental Cell , Cayuso et al (2016) demonstrate an active role of the endoderm in this process, challenging the prior view that the endoderm is passively pushed by the mesoderm. …”

“…It has been shown that asymmetric movement of the mesoderm, acting through the extracellular matrix between the endoderm and mesoderm, pushes the endoderm tube towards one side of the developing embryo (Kurpios, et al, 2008; Horne-Badovinac, et al, 2003). In this issue of Developmental Cell , Cayuso et al (2016) reveal an active role for the endoderm in the positioning of the liver in zebrafish.…”

“…Cayuso et al (2016) focused on the liver, an organ with an early and prominent loop to the left. To explore the extent to which cell shape changes and movements of the endoderm-derived hepatoblasts are important during normal hepatic budding and positioning, Cayuso et al (2016) used time-lapse confocal microscopy and rigorous quantification to analyze cell movement and shape at different stages of hepatic development. They observed that hepatoblasts first undergo elongation along the anterior-posterior axis and then collectively migrate leftward to aggregate into the liver bud.…”

“…While Ephrin/Eph signaling has recently been implicated in left-right pattern establishment in the zebrafish organizer, its role in later stages of left-right asymmetry had not been explored (Zhang, et al, 2016). Cayuso and colleagues (2016) found that the EphrinB1 ligand is one of the first genes expressed in hepatic progenitors, whereas its receptor, EphB3b , is subsequently restricted to the lateral plate mesoderm. Inactivation of either the ligand or receptor led to defective hepatoblast positioning, without affecting liver progenitor cell number or specification.…”

Meeting report − Intercellular interactions in context: towards a mechanistic understanding of cells in organs

“…Elke Ober (DanStem, University of Copenhagen, Denmark) proposed a new mechanism of left−right asymmetry, in which repulsive cues between the endoderm and mesoderm position the developing liver (Cayuso et al, 2016), and Aaron Johnson (University of Colorado, Denver, CO) showed that multiple repulsive signals also direct myofibre morphogenesis (Williams et al, 2015). At the molecular level, Dan Fletcher (University of California, Berkeley, CA) presented evidence that protein exclusion at membrane interfaces can play an essential role in signalling and fusion at membrane interfaces (Schmid et al, 2016).…”