Functions of c-jun in liver and heart development

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.