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, 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.

[1]  P. Krieg,et al.  The simultaneous extraction of high-molecular-weight DNA and of RNA from solid tumors. , 1983, Analytical biochemistry.

[2]  D. Kulesh,et al.  Activation of an intron enhancer within the keratin 18 gene by expression of c-fos and c-jun in undifferentiated F9 embryonal carcinoma cells. , 1990, Genes & development.

[3]  E. Bossy‐Wetzel,et al.  Induction of apoptosis by the transcription factor c‐Jun , 1997, The EMBO journal.

[4]  G. Michalopoulos,et al.  Molecular cloning and characterization of cDNA encoding mouse hepatocyte growth factor. , 1993, Biochimica et biophysica acta.

[5]  B. Spiegelman,et al.  Pleiotropic effects of a null mutation in the c-fos proto-oncogene , 1992, Cell.

[6]  K. Zatloukal,et al.  Evaluation of different RNA standards for quantitative reverse transcription PCR: possible pitfalls and strategies for avoidance , 1997 .

[7]  P. Seglen.  Preparation of isolated rat liver cells. , 1976, Methods in cell biology.

[8]  J. Stolarov,et al.  Programmed cell death in the absence of c-Fos and c-Jun. , 1996, Development.

[9]  E. Wagner,et al.  Control of cell cycle progression by c-Jun is p53 dependent. , 1999, Genes & development.

[10]  L. Lau,et al.  A gene activated by growth factors is related to the oncogene v-jun. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[11]  G. Crabtree,et al.  Molecular cloning, functional expression, and chromosomal localization of mouse hepatocyte nuclear factor 1. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[12]  K. Umesono,et al.  Jun-Fos and receptors for vitamins A and D recognize a common response element in the human osteocalcin gene , 1990, Cell.

[13]  K. Zatloukal,et al.  High molecular weight component of Mallory bodies detected by a monoclonal antibody. , 1990, Laboratory investigation; a journal of technical methods and pathology.

[14]  E. Dzierzak,et al.  Mouse embryonic hematopoiesis. , 1995, Trends in genetics : TIG.

[15]  N. Adey,et al.  Nucleotide sequence of the BALB/c mouse beta-globin complex. , 1989, Journal of molecular biology.

[16]  R. Tjian,et al.  Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements , 1987, Cell.

[17]  A. Copp,et al.  Development of a lethal congenital heart defect in the splotch (Pax3) mutant mouse. , 1997, Cardiovascular research.

[18]  E. Wagner,et al.  c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. , 1994, Science.

[19]  E. Wagner,et al.  Strain-dependent epithelial defects in mice lacking the EGF receptor. , 1995, Science.

[20]  L. Rubin,et al.  A c-jun dominant negative mutant protects sympathetic neurons against programmed cell death , 1995, Neuron.

[21]  M. Koury,et al.  Erythropoietin messenger RNA levels in developing mice and transfer of 125I-erythropoietin by the placenta. , 1988, The Journal of clinical investigation.

[22]  E. Robertson.  Teratocarcinomas and embryonic stem cells : a practical approach , 1987 .

[23]  J. Rossant,et al.  Mouse mutants and cardiac development: new molecular insights into cardiogenesis. , 1996, Circulation research.

[24]  V. Desmet.  Pathogenesis of Ductal Plate Abnormalities , 1998 .

[25]  B. Spiegelman,et al.  A null mutation at the c-jun locus causes embryonic lethality and retarded cell growth in culture. , 1993, Genes & development.

[26]  F. Bosch,et al.  Two genetically defined trans-acting loci coordinately regulate overlapping sets of liver-specific genes , 1990, Cell.

[27]  P. Chambon,et al.  Activation of the ovalbumin gene by the estrogen receptor involves the Fos-Jun complex , 1990, Cell.

[28]  E. Wagner,et al.  JunB is essential for mammalian placentation , 1999, The EMBO journal.

[29]  C. Hutchison,et al.  Nucleotide sequence of the BALB/c mouse β-globin complex , 1989 .

[30]  V. Desmet,et al.  Ludwig symposium on biliary disorders--part I. Pathogenesis of ductal plate abnormalities. , 1998, Mayo Clinic proceedings.

[31]  M. Kirby,et al.  Role of Neural Crest in Congenital Heart Disease , 1990, Circulation.

[32]  M. Nozaki,et al.  Isolation of endo A cDNA from mouse 8-cell stage embryos. , 1988, Biochemical and biophysical research communications.

[33]  E. Wagner,et al.  Bone and haematopoietic defects in mice lacking c-fos , 1992, Nature.

[34]  L. Matrisian,et al.  Growth factors regulate transin gene expression by c-fos-dependent and c-fos-independent pathways. , 1988, Science.

[35]  Rudolf Jaenisch,et al.  Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor , 1995, Cell.

[36]  R. Oshima,et al.  Molecular cloning and characterization of the Endo B cytokeratin expressed in preimplantation mouse embryos. , 1986, The Journal of biological chemistry.

[37]  D. Nathans,et al.  jun-D: a third member of the jun gene family. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[38]  M. Mattei,et al.  Structure and mapping of the fosB gene. FosB downregulates the activity of the fosB promoter. , 1992, Nucleic acids research.

[39]  L. Stanton,et al.  Nucleotide sequence comparison of normal and translocated murine c-myc genes , 1984, Nature.

[40]  E. Wagner,et al.  c-Jun is essential for normal mouse development and hepatogenesis , 1993, Nature.

[41]  M. Kirby,et al.  Neural crest and cardiovascular patterning. , 1995, Circulation research.

[42]  M. Prystowsky,et al.  Glyceraldehyde-3-phosphate dehydrogenase mRNA is a major interleukin 2-induced transcript in a cloned T-helper lymphocyte. , 1990, Gene.

[43]  D. Nathans,et al.  Induction of protooncogene c-jun by serum growth factors. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[44]  A. Nienhuis,et al.  Tandem AP-1-binding sites within the human beta-globin dominant control region function as an inducible enhancer in erythroid cells. , 1990, Genes & development.

[45]  Stephan Gebel,et al.  Antitumor promotion and antiinflammation: Down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone , 1990, Cell.

[46]  M. Kirby,et al.  Pathogenesis of persistent truncus arteriosus and dextroposed aorta in the chick embryo after neural crest ablation. , 1987, Circulation.

[47]  S. Law,et al.  The rate of molecular evolution of alpha-fetoprotein approaches that of pseudogenes. , 1985, Molecular biology and evolution.

[48]  T. Curran,et al.  Analysis of FBJ-MuSV provirus and c-fos (mouse) gene reveals that viral and cellular fos gene products have different carboxy termini , 1983, Cell.

[49]  S. Tapscott,et al.  Functional antagonism between c-Jun and MyoD proteins: A direct physical association , 1992, Cell.

[50]  D. Srivastava,et al.  Molecular Pathways Controlling Heart Development , 1996, Science.

[51]  Richard A. Ashmun,et al.  Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle , 1991, Cell.

[52]  E. Wagner,et al.  A strain‐independent postnatal neurodegeneration in mice lacking the EGF receptor , 1998, The EMBO journal.

[53]  C. Shoemaker,et al.  Murine erythropoietin gene: cloning, expression, and human gene homology , 1986, Molecular and cellular biology.

[54]  E. Wagner,et al.  Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation , 1999, Nature Genetics.

[55]  S. Estus,et al.  Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis , 1994, The Journal of cell biology.

[56]  P. Herrlich,et al.  12-O-tetradecanoyl-phorbol-13-acetate induction of the human collagenase gene is mediated by an inducible enhancer element located in the 5'-flanking region , 1987, Molecular and cellular biology.