Functions of c-Jun in liver and heart development.
Functions of c-Jun in liver and heart development.
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DOI：
10.1083/jcb.145.5.1049
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发表时间：
1999-05-31
影响因子：
7.8
通讯作者：
Zatloukal, K
中科院分区：
文献类型：
--
作者：
Eferl, R;Sibilia, M;Hilberg, F;Fuchsbichler, A;Kufferath, I;Guertl, B;Zenz, R;Wagner, E F;Zatloukal, K
缺乏AP-1转录因子c-Jun的小鼠在胚胎期E13.0左右死亡，但对受影响的细胞类型以及胚胎致死的原因知之甚少。在这里，我们表明，一部分突变E13.0胎肝表现出广泛的造血细胞和肝母细胞凋亡，而15个mRNA的表达，包括白蛋白，角蛋白18，肝细胞核因子1，β-珠蛋白，和促红细胞生成素，其中一些是公认的AP-1的靶基因，不受影响。突变肝脏中造血细胞的凋亡很可能不是由于细胞自主性缺陷，因为c-jun −/−胎肝细胞能够重建致死辐射受体小鼠的所有造血区室。嵌合体的发育分析显示c-jun −/− ES细胞衍生物对胎儿肝脏的贡献，但对成人肝脏没有贡献，这表明c-Jun在肝细胞周转中的作用。这与c-jun −/−胎儿的原代肝细胞培养物中发现的有丝分裂率降低和凋亡率增加一致。此外，c-Jun在心脏发育中的新功能被发现。c-jun −/−胎儿的心脏流出道显示出类似于人类持续性动脉干疾病的畸形。因此，c-jun突变胎儿的致死性最有可能是由于多效性缺陷，反映了c-Jun在发育中的功能多样性，例如在神经嵴细胞功能、维持肝造血和调节细胞凋亡中的作用。
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.