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© The Rockefeller University Press, 0021-9525/1999//1049 $5.00
The Journal of Cell Biology, Volume 145, Number 5, , 1999 1049-1061

Regular Articles

Functions of c-Jun in Liver and Heart Development



Robert Eferl*, Maria Sibilia{ddagger}, Frank Hilberg§, Andrea Fuchsbichler*, Iris Kufferath*, Barbara Guertl*, Rainer Zenz*, Erwin F. Wagner{ddagger}, and Kurt Zatloukal*

* Department of Pathology, University of Graz, A-8036 Graz, Austria; {ddagger} Research Institute of Molecular Pathology, A-1030 Vienna, Austria; and § Boehringer Ingelheim, A-1121 Vienna, Austria

Mice lacking the AP-1 transcription factor c-Jun die around embryonic day E13.0 but little is known about the cell types affected as well as the cause of embryonic lethality. Here we show that a fraction of mutant E13.0 fetal livers exhibits extensive apoptosis of both hematopoietic cells and hepatoblasts, whereas the expression of 15 mRNAs, including those of albumin, keratin 18, hepatocyte nuclear factor 1, β-globin, and erythropoietin, some of which are putative AP-1 target genes, is not affected. Apoptosis of hematopoietic cells in mutant livers is most likely not due to a cell-autonomous defect, since c-jun–/– fetal liver cells are able to reconstitute all hematopoietic compartments of lethally irradiated recipient mice. A developmental analysis of chimeras showed contribution of c-jun–/– ES cell derivatives to fetal, but not to adult livers, suggesting a role of c-Jun in hepatocyte turnover. This is in agreement with the reduced mitotic and increased apoptotic rates found in primary liver cell cultures derived from c-jun–/– fetuses. Furthermore, a novel function for c-Jun was found in heart development. The heart outflow tract of c-jun–/– fetuses show malformations that resemble the human disease of a truncus arteriosus persistens. Therefore, the lethality of c-jun mutant fetuses is most likely due to pleiotropic defects reflecting the diversity of functions of c-Jun in development, such as a role in neural crest cell function, in the maintenance of hepatic hematopoiesis and in the regulation of apoptosis.

Key Words: apoptosis • neural crest • hematopoiesis • knockout • truncus arteriosus persistens

Abbreviations used in this paper: AP-1, activating protein 1; Cx 43, connexin 43; ES cells, embryonic stem cells; GPI, glucose phosphate isomerase; HGF, hepatocyte growth factor; HNF-1, hepatocyte nuclear factor 1; RT-PCR, reverse transcriptase PCR; TUNEL, TdT-mediated dUTP nick-end labeling.

The technical assistance of Ms. C. Stumptner is gratefully acknowledged.


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