13 November 2016
Organ asymmetry: How the liver finds its place
POSITIONING INTERNAL ORGANS IN THE BODY
Research by the Ober group, published in the latest issue of Developmental Cell, investigates the development of the liver and how it is positioned asymmetrically along the left-right body axis. During embryonic development, each internal organ is built by a group of specific progenitor cells. They first form at the midline of the embryo and move left or right to efficiently place each organ in the body cavity. Progenitor cells therefore need to be motile, receive directions where to move and finally interact with other cells as they navigate through the embryo to their final destination and establish the organ.
Focussing on the liver, an essential metabolic organ, the Ober group asked: what controls the co-ordinated and asymmetric movement of liver progenitor cells in development? For answering this question they use zebrafish embryos, because unlike many other species they are transparent and allow observing the internal organs as they develop. In their recent paper, they challenge a previously suggested hypothesis whereby neighbouring tissues push liver progenitor cells to the left side of the body. By filming labelled liver progenitors (see movie) and analysing their movement, they demonstrate that they actively migrate away from the gut to form an asymmetric liver. This raised the question of how they know where to migrate. Rather than pushing the liver progenitors, the neighbouring cells on the right side present them with a repulsive signal that tells them to move to the left. Jordi Cayuso and colleagues discovered that the liver progenitor cells form short and long cell extensions to explore their surroundings and when they contact one of these neighbouring cells on the right they immediately stop and move to the left. They also identified the ‘signal-reception’ system that controls this directional migration. EphrinB1 and EphB3b are two proteins that mediate this interaction between the liver and neighbouring cells. EphrinB1 is on the surface of liver cells and detects EphB3b at the surface of neighbouring cells when they make contact. In the absence these proteins the directional migration of progenitor cell is disrupted and leads to a positioning defect with the liver at the midline.
The findings of the Ober group help us to understand the mechanisms of left-right organ positioning and associated human disorders, such as situs inversus and heterotaxy. In these genetic conditions the majority of internal organs are misaligned, either in reverse position or randomly arranged. Heterotaxy often includes multiple organ defects that generally require surgery. Given that cell motility is a hallmark of invasive cancer cells, insights from this study may also help to understand the spreading of transformed cells.
Migrating liver progenitors form cellular protrusions during the early stages of liver formation. Transgenic UAS:lyn-Citrine labels cell membranes. Images were taken every 23,5 min and the monitored period is equivalent to 24 -34 hours after fertilisation. Scale bar - 40μm.
About the authors
Jordi Cayuso (on the right) is a developmental biologist with an interest in the mechanisms that shape tissues and embryos. He was a postdoc in the Ober group, where he focussed on the role of Ephrin/Eph signalling in liver morphogenesis. Recently, he is asking whether similar mechanisms govern hindbrain development in the Wilkinson laboratory at the Crick. His fascination and expertise in genetically engineering the zebrafish genome using the CRISPR/Cas9 system are a well-known secret.
Aliaksandr Dzementsei (on the left) is a postdoc at the Ober group. He is interested in biophysical and biomechanical mechanisms underlying cell migration and organ formation. As a developmental biologist, he works in close collaboration with physicists and bioinformatians to develop new tools and assays which will help to address fundamental questions in biology using advanced quantitative methods.
Kristeligt Dagblad: Forskere afslører, at leveren vandrer
Cayuso, Jordi, Aliaksandr Dzementsei, Johanna C Fischer, Gopal Karemore, Sara Caviglia, Josefin Bartholdson, Gavin J Wright & Elke A Ober (2016). EphrinB1/EphB3b Coordinate Bidirectional Epithelial-Mesenchymal Interactions Controlling Liver Morphogenesis and Laterality. Developmental Cell, 39(3), 316-328, doi:10.1016/j.devcel.2016.10.009.