Mice lacking the AP-1 transcription factor c-Jun die around embryonic day E
13.0 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 hepato
blasts, whereas the expression of 15 mRNAs, including those of albumin, ker
atin 18, hepatocyte nuclear factor 1, beta-globin, and erythropoietin, some
of which are putative AP-1 target genes, is not affected. Apoptosis of hem
atopoietic cells in mutant livers is most likely not due to a cell-autonomo
us defect, since c-jun(-/-) fetal liver cells are able to reconstitute all
hematopoietic compartments of lethally irradiated recipient mice. A develop
mental analysis of chimeras showed contribution of c-jun(-/-) ES cell deriv
atives to fetal, but not to adult livers, suggesting a role of c-Jun in hep
atocyte turnover. This is in agreement with the reduced mitotic and increas
ed apoptotic rates found in primary liver cell cultures derived from c-jun(
-/-) fetuses. Furthermore, a novel function for c-Jun was found in heart de
velopment. The heart outflow tract of c-jun(-/-) fetuses show malformations
that resemble the human disease of a truncus arteriosus persistens. Theref
ore, the lethality of c-jun mutant fetuses is most likely due to pleiotropi
c defects reflecting the diversity of functions of c-Jun in development, su
ch as a role in neural crest cell function, in the maintenance of hepatic h
ematopoiesis and in the regulation of apoptosis.