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.
Over the last ten years studies have shown that FGF and BMP growth factors secreted from the heart mesoderm induce the liver from a subset of the foregut endoderm tissue. As a result the undifferentiated liver precursors cells known as “hepatoblasts” delaminate from the foregut epithelium and invade the adjacent mesenchyme to form the growing liver bud– a bulb of tissue emerging from the primitive gut tube (Fig. 2). However, there are a number of important steps in this process that are not well understood and which our research is attempting to address using frog and mouse embryos as experimental models.
Illustrations
Figure 1 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.
Figure 2 (A) A transgenic mouse embryo (foxa3cre;Rosa26R) at 9.5 days of development stained for β-galactosidase expression in the gut epithelium and liver diverticulum (l.d.), from which the liver bud grows. (B) A transverse section through the liver bud of the embryo in (A) stained with anti-HNF4α antibodies, shows the endoderm in blue and the HNF4α-expressing hepatoblasts invading the mesenchyme.
- The earlier events that make the foregut progenitor cell competent to become liver in respond to growth factors from the heart mesoderm are unclear. We are testing the hypothesis that this is controlled in part by the differential Wnt signaling events that pattern the endoderm. We are trying to understand role of Wnt-antagonists in this process and how early endoderm patterning is linked with subsequent organ induction.
- The genetic program that is initiated in the liver progenitor cells by FGF and BMP signals from the mesoderm are unknown. Using the microsurgery of foregut tissue and global gene expression analysis we have uncovered a number of novel target gene and we are characterizing their function.
- There is evidence that different levels of FGF, BMP and Wnt growth factor signaling directs some foregut cells to become liver while nearby cells become pancreas or lung. Moreover, it is increasingly clear that the same growth factors can have different, even opposite, roles at different times in development. We are investigating the mystery of how the FGF, BMP and Wnt signaling pathways interact and how they activities are regulated in time and space in the dynamically developing embryos.
The results of this proposal will provide novel information on the molecular mechanisms governing early hepatic development.
Related Publications:
Li Y, Rankin SA, Sinner D, Kenney, AP, Krieg PA, Zorn AM. (2008) Sfrp5 coordinates foregut specification and morphogenesis by antagonizing both canonical and non-canonical Wnt11 signaling. Genes & Development 22:3050-63.
McLin VA, Rankin SA, Zorn AM. (2007) Repression of Wnt/beta-catenin signaling in the anterior endoderm is essential for liver and pancreas development. Development 134:2207-2217.
Zorn AM, Mason J. (2001) Gene expression in the embryonic Liver of Xenopus. Mech Dev 103:153-157.
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@cchmc.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.
