Mrf4 determines skeletal muscle identity in Myf5:Myod double-mutant mice
Mrf4 determines skeletal muscle identity in Myf5:Myod double-mutant mice
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DOI：
10.1038/nature02876
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发表时间：
2004-09-23
期刊：
影响因子：
64.8
通讯作者：
Tajbakhsh, S
中科院分区：
文献类型：
--
作者：
Kassar-Duchossoy, L;Gayraud-Morel, B;Tajbakhsh, S
在脊椎动物中，骨骼肌是从干细胞获得细胞命运的模型（1）。基本螺旋-环-螺旋生肌调节因子（MRF）家族的两个决定因子Myf 5和Myod被认为指导这种转变，因为双突变小鼠完全缺乏骨骼肌纤维和成肌细胞（2-4）。在缺乏这些因子的情况下，祖细胞保持多能性，并可以改变其命运（5，6）。基因靶向研究揭示了这些基因与其他MRF基因Mrf 4和肌细胞生成素之间的层次关系，后者被认为是分化基因（7）。在这里，我们显示，使用三个Myf 5突变体的等位基因系列，差异地影响遗传连锁的Mrf 4基因的表达，骨骼肌存在于新的Myf 5：Myod双无效小鼠中，只有当Mrf 4表达不受损害时。这一发现与普遍认为肌源性身份仅由Myf 5和Myod赋予的观点相矛盾，并将Mrf 4确定为决定基因。我们修改了MRFs的上位关系，其中Myf 5和Mrf 4都在Myod的上游起作用，以指导胚胎多能细胞进入肌源性谱系。
In vertebrates, skeletal muscle is a model for the acquisition of cell fate from stem cells(1). Two determination factors of the basic helix - loop - helixmyogenic regulatory factor (MRF) family, Myf5 and Myod, are thought to direct this transition because double-mutant mice totally lack skeletal muscle fibres and myoblasts(2-4). In the absence of these factors, progenitor cells remain multipotent and can change their fate(5,6). Gene targeting studies have revealed hierarchical relationships between these and the other MRF genes, Mrf4 and myogenin, where the latter are regarded as differentiation genes(7). Here we show, using an allelic series of three Myf5 mutants that differentially affect the expression of the genetically linked Mrf4 gene, that skeletal muscle is present in the new Myf5: Myod double- null mice only when Mrf4 expression is not compromised. This finding contradicts the widely held view thatmyogenic identity is conferred solely byMyf5 and Myod, and identifies Mrf4 as a determination gene. We revise the epistatic relationship of the MRFs, in which both Myf5 and Mrf4 act upstream of Myod to direct embryonic multipotent cells into the myogenic lineage.