Sall4 Is Essential for Stabilization, But Not for Pluripotency, of Embryonic Stem Cells by Repressing Aberrant Trophectoderm Gene Expression
Sall4 Is Essential for Stabilization, But Not for Pluripotency, of Embryonic Stem Cells by Repressing Aberrant Trophectoderm Gene Expression
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DOI：
10.1002/stem.14
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发表时间：
2009-01-01
期刊：
影响因子：
5.2
通讯作者：
Nishinakamura, Ryuichi
中科院分区：
文献类型：
--
作者：
Yuri, Shunsuke;Fujimura, Sayoko;Nishinakamura, Ryuichi
SALL4是常染色体显性遗传性疾病Okihiro综合征的致病基因的小鼠同源物。我们先前的研究表明，Sall4缺失会导致围着床期的致命性死亡，并且Sall4缺失的胚胎干细胞在饲养层细胞上培养时，增殖不良且具有完整的多能性。在此，我们报道，在没有饲养层细胞的情况下，Sall4缺失的ES细胞表达滋养外胚层标记CDX2，但长期保持未分化状态，对Oct3/4的表达影响最小。体内无饲养层的Sall4缺失的ES细胞仅对内细胞团和外胚层有贡献，表明这些细胞仍然保持多能性，并不完全致力于滋养外胚层。这些表型可能是由于CDX2启动子的去抑制引起的，而CDX2启动子通常被Sall4和Mi2/NuRD HDAC复合体抑制。然而，在没有Sall4的情况下，细胞增殖受到损害，G1期延长，这表明Sall4在细胞周期控制中另有作用。虽然SALL1，也是一个SALL1家族基因，已知在体内与Sall4基因相互作用，但SALL1缺失的ES细胞没有明显的缺陷，与Sall4缺失的ES细胞相比，缺乏SALL1和Sall4的ES细胞没有恶化。这表明Sall4在ES细胞中具有独特的作用。因此，尽管Sall4不参与多能性的中枢机制，但它通过抑制异常的滋养外胚层基因表达来稳定ES细胞。干细胞2009；27：796-805
Sall4 is a mouse homolog of a causative gene of the autosomal dominant disorder Okihiro syndrome. We previously showed that the absence of Sall4 leads to lethality during peri-implantation and that Sall4-null embryonic stem (ES) cells proliferate poorly with intact pluripotency when cultured on feeder cells. Here, we report that, in the absence of feeder cells, Sall4-null ES cells express the trophectoderm marker Cdx2, but are maintained for a long period in an undifferentiated state with minimally affected Oct3/4 expression. Feeder-free Sall4-null ES cells contribute solely to the inner cell mass and epiblast in vivo, indicating that these cells still retain pluripotency and do not fully commit to the trophectoderm. These phenotypes could arise from derepression of the Cdx2 promoter, which is normally suppressed by Sall4 and the Mi2/NuRD HDAC complex. However, proliferation was impaired and G1 phase prolonged in the absence of Sall4, suggesting another role for Sall4 in cell cycle control. Although Sall1, also a Sall family gene, is known to genetically interact with Sall4 in vivo, Sall1-null ES cells have no apparent defects and no exacerbation is observed in ES cells lacking both Sall1 and Sall4, compared with Sall4-null cells. This suggests a unique role for Sall4 in ES cells. Thus, though Sall4 does not contribute to the central machinery of the pluripotency, it stabilizes ES cells by repressing aberrant trophectoderm gene expression. STEM CELLS 2009;27:796-805