Retinoic acid stimulates myocardial expansion by induction of hepatic erythropoietin which activates epicardial Igf2
Retinoic acid stimulates myocardial expansion by induction of hepatic erythropoietin which activates epicardial Igf2
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DOI：
10.1242/dev.054239
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发表时间：
2011-01-01
期刊：
影响因子：
4.6
通讯作者：
Duester, Gregg
中科院分区：
文献类型：
--
作者：
Brade, Thomas;Kumar, Sandeep;Duester, Gregg
心外膜信号传导和 Rxra 是心室心肌致密区扩张所必需的。在这里，我们检查 Raldh2(-/-) 和 Rxra(-/-) 小鼠胚胎，以研究视黄酸 (RA) 信号在这一发育过程中的作用。 Raldh2 和 Rxra 突变体的心脏表型非常相似，其特征是心室致密区生长的显着缺陷。尽管Raldh2(-/-)心外膜和邻近心肌中的RA活性完全丧失，但Rxra(-/-)心脏中的RA活性并未丧失，这表明心外膜/心肌中的RA信号传导不是心肌致密区形成所必需的。我们探讨了非心脏组织中 RA 介导的靶基因转录是这一过程所必需的可能性。我们发现促红细胞生成素 (EPO)（一种与心肌扩张有关的分泌因子）的肝脏表达依赖于 Raldh2 和 Rxra。染色质免疫沉淀研究支持 Epo 作为胚胎肝脏中 RA 信号传导的直接靶点。用 EPO（而非 RA）处理心外膜细胞系会上调 Igf2。此外，Raldh2(-/-) 和 Rxra(-/-) 心脏均表现出心外膜中 Igf2 mRNA 的下调。 EPO 处理培养的 Raldh2(-/-) 心脏可恢复心外膜 Igf2 表达并挽救心室心肌细胞增殖。我们提出了一种关于 RA 介导的心肌扩张机制的新模型，其中 RA 直接诱导肝 Epo，导致心外膜 Igf2 激活，刺激致密区生长。该 RA-EPO-IGF2 信号轴协调肝脏造血与心脏发育。
Epicardial signaling and Rxra are required for expansion of the ventricular myocardial compact zone. Here, we examine Raldh2(-/-) and Rxra(-/-) mouse embryos to investigate the role of retinoic acid (RA) signaling in this developmental process. The heart phenotypes of Raldh2 and Rxra mutants are very similar and are characterized by a prominent defect in ventricular compact zone growth. Although RA activity is completely lost in Raldh2(-/-) epicardium and the adjacent myocardium, RA activity is not lost in Rxra(-/-) hearts, suggesting that RA signaling in the epicardium/myocardium is not required for myocardial compact zone formation. We explored the possibility that RA-mediated target gene transcription in non-cardiac tissues is required for this process. We found that hepatic expression of erythropoietin (EPO), a secreted factor implicated in myocardial expansion, is dependent on both Raldh2 and Rxra. Chromatin immunoprecipitation studies support Epo as a direct target of RA signaling in embryonic liver. Treatment of an epicardial cell line with EPO, but not RA, upregulates Igf2. Furthermore, both Raldh2(-/-) and Rxra(-/-) hearts exhibit downregulation of Igf2 mRNA in the epicardium. EPO treatment of cultured Raldh2(-/-) hearts restores epicardial Igf2 expression and rescues ventricular cardiomyocyte proliferation. We propose a new model for the mechanism of RA-mediated myocardial expansion in which RA directly induces hepatic Epo resulting in activation of epicardial Igf2 that stimulates compact zone growth. This RA-EPO-IGF2 signaling axis coordinates liver hematopoiesis with heart development.