Functions of c-Jun in liver and heart development.
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, beta-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.
Eferl
R
R
Department of Pathology, University of Graz, A-8036 Graz, Austria.
Sibilia
M
M
Hilberg
F
F
Fuchsbichler
A
A
Kufferath
I
I
Guertl
B
B
Zenz
R
R
Wagner
E F
EF
Zatloukal
K
K
D000818:Animals; D017209:Apoptosis; D005314:Embryonic and Fetal Development; D017353:Gene Deletion; D006321:Heart / Q000196:embryology* / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000473:pathology / Q000502:physiology; D008099:Liver / Q000196:embryology* / Q000473:pathology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology*
D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1