Scientists at the Francis Crick Institute have discovered the cell-cell interaction responsible for positioning the liver on one side of the body during zebrafish development.
Organ asymmetry relates to the internal position of an organ, for example the liver and the heart are asymmetrically positioned in humans. During development of the embryo, each organ is built by a group of specific early-stage cells, called progenitor cells. Initially these cells form symmetrically, at the midline of the embryo, before navigating left or right through the embryo, positioning the organ in its final location.
Refuting a previously suggested hypothesis, the scientists show that liver progenitor cells are not 'pushed' into an asymmetric position by neighbouring cells in the surrounding mesoderm, rather they actively move to the left, away from the midline.
The new study, by researchers at the Crick and other institutes, demonstrates that this happens because the cells to the right of the liver progenitor cells give a repulsive signal that tells the liver cells to move to the left.
The team observed that liver progenitor cells formed cell extensions to explore their surroundings, and when they contacted one of the 'repulsive' cells to their right they immediately stopped and moved to the left.
The research also shows that the signalling mechanism responsible for this cell-cell interaction is mediated by two proteins: EphrinB1 on the surface of the liver cells and EphB3b on the surface of their neighbouring cells.
Jordi Cayuso is first author on the new paper. He is a senior researcher in David Wilkinson's group at the Crick. Previously he was a member of Elke Ober's group at the MRC's National Institute of Medical Research, one of the two institutes which merged to form the Crick.
Jordi says: "Our study challenges previous models suggesting that forces exerted by the mesoderm are pushing the liver to its final asymmetric position in the body. We uncover a more complex situation where bidirectional interactions between liver precursors and the surrounding mesoderm are responsible for the coordinated migration and morphogenesis of both tissues."
In humans there are a number of rare genetic disorders, for example situs inversus and heterotaxy, where the majority of internal organs are incorrectly aligned, either in a reversed position or randomly arranged.
These research findings advance our understanding of the mechanisms underlying these developmental disorders. Insights from this study may also help us to better understand how cancer spreads, by improving our understanding of cell motion and movement.
The paper, EphrinB1/EphB3b Coordinate Bidirectional Epithelial-Mesenchymal Interactions Controlling Liver Morphogenesis and Laterality, is published in Developmental Cell.
