Liver Formation
One of our long-term goals is to elucidate the molecular program controlling liver development. The liver provides many essential functions and numerous liver pathologies are so life threatening that transplantation is the only option.
Despite its physiological importance the molecular basis of liver development is poorly understood. A better understanding of liver development will provide insight into congenital liver disease and facilitate efforts to produce therapeutically useful hepatic tissue from stem cells.
In vitro mouse explant studies suggest that FGF and BMP signals from the cardiogenic mesoderm induce the liver from the ventral foregut endoderm, while unknown inhibitory signals from the posterior mesoderm prevent hepatic development in the hindgut endoderm. However, this model has not been tested in vivo. Furthermore, the earlier events that make the foregut competent to respond to these cardiac signals and the genetic program initiated by liver induction are unknown.
Our lack of knowledge stems mostly from the fact that these events occur shortly after gastrulation, when mammalian embryos are rather inaccessible. We are combining the experimental advantages of Xenopus, which has proven exceptionally useful for studying early development and established mouse embryos explant techniques, to address these critical unresolved steps in early liver development.
Illustration
Figure 1 A On the left, one-day-old Xenopus embryos stained for the expression of the homeobox gene Hex (black staining) indicates the presumptive liver and thyroid region prior to differentiation. The histological section on the right shows the growing liver-bud of a 3 day old embryo.
Our preliminary experiments indicate that liver development is conserved between Xenopus and mammals. Secondly, our preliminary data leads us to hypothesize that Wnt signaling regulates hepatic competence of the endoderm. We propose that Wnt ligands from the posterior mesoderm inhibit hepatic development in the hindgut, while Wnt-antagonists in gastrula anterior endoderm make it competent to respond to liver induction. There are three major unanswered questions we are addressing at the moment
- While in vitro data implicate FGFs and BMPs as liver inducers, their precise role in vivo has not been determined and may be more complicated than predicted. We are testing the current model of liver induction and determine the in vivo role of FGF and BMP signaling in Xenopus liver specification.
- The earlier patterning steps that make the anterior endoderm competent to initiate hepatogenesis in response to liver induction are not understood. We are testing if Wnt signaling regulates hepatic competence and foregut development.
- It is clear that there must be more genes that just FGFs and BMPs regulating liver specification. We are using DNA microarrays and functional screens to identify novel genes involved in liver specification.
The results of this proposal will provide novel information on the molecular mechanisms governing early hepatic development.
Related Publications:
Zorn AM and Mason J (2001) Gene expression in the embryonic Liver of Xenopus. Mech Dev 103:153-157.
McLin VA, Rankin SA and Zorn AM (2007) Repression of Wnt/beta-catenin signaling in the anterior endoderm is essential for liver and pancreas development. Development 134: 2207-2217.
If you would like to join our research team, contact the Zorn Laboratory. The Zorn Lab is part of the Division of Developmental Biology at Cincinnati Children's Research Foundation. The lab is located in Location R (Research Foundation Building), Room 2509.
Division of Developmental Biology
Cincinnati Children's Research Foundation
Cincinnati, OH 45229-3039
E-mail Aaron.Zorn@chmcc.org
Phone 513-636-3770
Fax 513-636-4317 Interested in joining us as a student or a postdoc? Learn more about postdoctoral training and graduate student opportunities at Cincinnati Children's.
