MRC National Institute for Medical Research, London
Science for Health
Wnt genes coordinate liver and pancreas organogenesis
28 July 2011
How neighbouring tissues become distinct is a fundamental question in developmental biology. Endodermal organs, such as the foregut-derived liver, pancreas and lung, are formed in close proximity to each other from a pool of multipotent endoderm. A number of factors are known to be involved in the development of these important organs, but the specific contributions of the Wnt pathway are only poorly understood. Analyses in mouse and chick have uncovered the spatially restricted expression of numerous Wnt pathway components along the digestive tract, suggesting region-specific function in development. Several studies have implicated Wnt signalling in different steps of digestive system organogenesis, through the manipulation of intracellular signaling components. However, very few endogenous ligands and receptors have been associated with specific aspects of endodermal organogenesis.
Morgane Poulain and Elke Ober (pictured) from NIMR’s Division of Developmental Biology have investigated the role of two closely related Wnt ligands in foregut-derived organ development. Using loss-of-function approaches in zebrafish they have demonstrated that the combined activity of Wnt2 and Wnt2bb is essential for hepatic specification and subsequent proliferation of newly-specified liver progenitors. Importantly, transient overexpression of either ligand led to an expansion of the liver progenitor pool at the expense of the adjacent pancreas and anterior intestine. The researchers have started to unravel the underlying mechanism by showing that the endodermal Frizzled5 receptor interacts with mesodermally-derived Wnt2bb and Wnt2 in hepatoblast formation, indicating that Frizzled5 mediates the broader competence of the alimentary canal to respond to spatially restricted hepatogenic Wnt2/2bb signals.
In addition, their work has shown that the lack of Wnt2 and Wnt2bb results in severe reduction in the size of the swim bladder, the structural homologue of the murine lung. These are some of the first factors for swim bladder formation to be identified. Overall, these findings provide functional data supporting the idea that a Wnt ‘code’ governs digestive system development.
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Excess wnt2bb promotes liver formation from multipotent foregut endoderm at the expense of the ventral pancreas. Specifically, transient wnt2bb-overexpression at the time of liver specification results in an enlarged hepatic domain (red) and a severe decrease of pancreatic exocrine tissue (green). Panels show ventral views of the foregut area of the zebrafish digestive system with anterior to the top.
This study shows in vivo that the nascent digestive tract exhibits a broad competence to respond to hepatogenic signals and that altering their precise spatial and temporal expression consequently disrupts the fine balance between the different organ progenitor pools. This finding may have broader implications for stem cell biology and regenerative medicine. Furthermore, our findings are interesting in the light of a recent study showing that Wnt2/2b signaling in mouse controls the specification of lung progenitors, while their requirement for liver progenitor formation is not entirely clear, and is possibly of lesser importance. In the mice the lung and liver are separated by the stomach, whereas zebrafish are stomach-less, supporting the intriguing notion that the same positional information is interpreted differently due to changing digestive requirements that are paralleled by a change in the digestive anatomy.
Elke Ober
Original article
Interplay between Wnt2 and Wnt2bb controls multiple steps of early foregut-derived organ development (2011)
Morgane Poulain and Elke Ober
Development, 138:3557-3568. Pubmed abstract
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