Placental rescue reveals a sole requirement for c-Myc in embryonic erythroblast survival and hematopoietic stem cell function
Placental rescue reveals a sole requirement for c-Myc in embryonic erythroblast survival and hematopoietic stem cell function
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DOI：
10.1242/dev.022707
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发表时间：
2008-07-15
期刊：
影响因子：
4.6
通讯作者：
Trumpp, Andreas
中科院分区：
文献类型：
--
作者：
Dubois, Nicole C.;Adolphe, Christelle;Trumpp, Andreas
c-Myc 蛋白在调节涉及细胞功能许多方面的大量基因的表达方面发挥着关键作用。与这一观点一致，缺乏 c-myc 基因的胚胎表现出严重的发育缺陷并在妊娠中期之前死亡。在这里，我们表明，Sox2Cre 介导的条件性 c-myc(flox) 等位基因的删除，特别是在外胚层（因此滋养外胚层和原始内胚层结构是野生型），可以挽救先前在 c-myc 敲除胚胎中表征的大多数发育异常，表明它们是继发性缺陷，是由于胎盘功能不全而产生的。外胚层限制的 c-Myc 缺失胚胎形态正常，没有表现出任何明显的增殖缺陷。尽管如此，这些胚胎严重贫血，并在 E12 之前死亡。 c-Myc 缺陷胚胎表现出胎儿肝脏发育不全、红细胞前体细胞凋亡和功能缺陷的最终造血干/祖细胞。造血或肝细胞谱系中 c-myc(flox) 的特异性缺失验证了胚胎本身中 c-Myc 的造血特异性需求，并提供了支持造血和肝脏发育之间协同作用的体内证据。我们的结果首次揭示了 c-Myc 的生理水平对于细胞存活至关重要，并证明与大多数其他胚胎谱系相比，有红细胞和造血干/祖细胞特别依赖于 c-Myc 功能。
The c-Myc protein has been implicated in playing a pivotal role in regulating the expression of a large number of genes involved in many aspects of cellular function. Consistent with this view, embryos lacking the c-myc gene exhibit severe developmental defects and die before midgestation. Here, we show that Sox2Cre-mediated deletion of the conditional c-myc(flox) allele specifically in the epiblast (hence trophoectoderm and primitive endoderm structures are wild type) rescues the majority of developmental abnormalities previously characterized in c-myc knockout embryos, indicating that they are secondary defects and arise as a result of placental insufficiency. Epiblast-restricted c-Myc-null embryos appear morphologically normal and do not exhibit any obvious proliferation defects. Nonetheless, these embryos are severely anemic and die before E12. c-Myc-deficient embryos exhibit fetal liver hypoplasia, apoptosis of erythrocyte precursors and functionally defective definitive hematopoietic stem/progenitor cells. Specific deletion of c-myc(flox) in hemogenic or hepatocytic lineages validate the hematopoietic-specific requirement of c-Myc in the embryo proper and provide in vivo evidence to support a synergism between hematopoietic and liver development. Our results reveal for the first time that physiological levels of c-Myc are essential for cell survival and demonstrate that, in contrast to most other embryonic lineages, erythroblasts and hematopoietic stem/progenitor cells are particularly dependent on c-Myc function.