EphrinB1/EphB3b Coordinate Bidirectional Epithelial-Mesenchymal Interactions Controlling Liver Morphogenesis and Laterality.
Positioning 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.
Division of Developmental Biology, Mill Hill Laboratories, The Francis Crick Institute, London NW7 1AA, UK.
Jordi
J
Cayuso
Danish Stem Cell Center (DanStem), University of Copenhagen, 2200 Copenhagen N, Denmark.
Aliaksandr
A
Dzementsei
Division of Developmental Biology, Mill Hill Laboratories, The Francis Crick Institute, London NW7 1AA, UK.
Johanna C
JC
Fischer
Novo Nordisk Foundation Center for Protein Research, Protein Imaging Platform, University of Copenhagen, 2200 Copenhagen N, Denmark.
Gopal
G
Karemore
Danish Stem Cell Center (DanStem), University of Copenhagen, 2200 Copenhagen N, Denmark.
Sara
S
Caviglia
Wellcome Trust Sanger Institute, Cell Surface Signalling Laboratory, Cambridge CB10 1HH, UK.
Josefin
J
Bartholdson
Wellcome Trust Sanger Institute, Cell Surface Signalling Laboratory, Cambridge CB10 1HH, UK.
Gavin J
GJ
Wright
Division of Developmental Biology, Mill Hill Laboratories, The Francis Crick Institute, London NW7 1AA, UK; Danish Stem Cell Center (DanStem), University of Copenhagen, 2200 Copenhagen N, Denmark. Electronic address: elke.ober@sund.ku.dk.
Elke A
EA
Ober
D000818:Animals; D019521:Body Patterning; D002465:Cell Movement; D048430:Cell Shape; D036387:Ephrin-B1 / Q000378:metabolism*; D036389:Ephrin-B3 / Q000378:metabolism*; D004848:Epithelium / Q000196:embryology* / Q000378:metabolism; D007839:Functional Laterality; D008099:Liver / Q000196:embryology*; D008648:Mesoderm / Q000196:embryology* / Q000378:metabolism; D009024:Morphogenesis; D011554:Pseudopodia / Q000378:metabolism; D036081:Receptors, Eph Family / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism; D029961:Zebrafish Proteins / Q000378:metabolism*
C000620813:EphB3b protein, zebrafish; D036387:Ephrin-B1; D036389:Ephrin-B3; D029961:Zebrafish Proteins; D036081:Receptors, Eph Family
EphB3; EphrinB1; bidirectional; lateral plate mesoderm; liver; migration; morphogenesis; protrusion; repulsion; zebrafish