Department of Molecular Biology, Princeton University, Princeton, NJ 08554, USA.
Stem Cells. 2012 Jul;30(7):1496-508. doi: 10.1002/stem.1112.
The transcription factor E74-like factor 5 (Elf5) functions downstream of the prolactin receptor signaling pathway and plays an important role in mammary gland development. Using conditional mouse knockouts, we have previously shown that Elf5-null mammary glands exhibit a complete failure of alveologenesis during pregnancy. The Elf5-null developmental phenotype is mediated through alteration in the expression of several critical genes involved in alveologenesis, particularly those belonging to the JAK/STAT pathway. Here, we demonstrate that in addition to regulating terminal differentiation of alveolar cells, Elf5 also plays a critical role in determining cell fate and in regulating the stem/progenitor function of the mammary epithelium. Targeted deletion of Elf5 in the mammary glands leads to accumulation of cell types with dual luminal/basal properties such as coexpression of K8 and K14 and an increase in CD61(+) luminal progenitor population during pregnancy. Further interrogation suggests that the abnormal increase in K14(+) K8(+) cells may represent the CD61(+) luminal progenitors blocked in differentiation. Remarkably, Elf5 deficiency in mammary epithelium also triggers an increase of adult mammary stem activity as evidenced by the accumulation of mammary stem cell (MaSC)-enriched cell population in both pregnant and virgin mice and further confirmed by mammosphere and transplantation assays. Additional support for this phenotype comes from the enriched MaSC gene signature based on transcriptomic analysis of the Elf5-null mammary gland. Finally, our biochemical studies suggest that Elf5 loss leads to hyperactivation of the Notch signaling pathway, which might constitute in part, the underlying molecular mechanism for the altered cell lineage decisions in Elf5-null mammary epithelial cells.
转录因子 E74 样因子 5(Elf5)是催乳素受体信号通路的下游因子,在乳腺发育中发挥重要作用。我们之前使用条件性基因敲除小鼠模型证明,Elf5 缺失的乳腺在妊娠期间完全不能发生肺泡生成。Elf5 缺失的发育表型是通过改变几个关键基因的表达介导的,这些基因参与肺泡生成,特别是那些属于 JAK/STAT 通路的基因。在这里,我们证明了 Elf5 不仅调节肺泡细胞的终末分化,还在决定乳腺上皮细胞的命运和调节其干细胞/祖细胞功能方面发挥关键作用。在乳腺中靶向敲除 Elf5 会导致具有双腔/基底特性的细胞类型积累,例如 K8 和 K14 的共表达,以及妊娠期间 CD61(+)腔前体细胞群体的增加。进一步研究表明,异常增加的 K14(+) K8(+)细胞可能代表分化受阻的 CD61(+)腔前体细胞。值得注意的是,乳腺上皮细胞中 Elf5 的缺失也会触发成年乳腺干细胞活性的增加,这可以从妊娠和未孕小鼠中乳腺干细胞(MaSC)富集细胞群体的积累得到证明,并通过乳腺球体和移植实验进一步证实。基于 Elf5 缺失乳腺转录组分析的 MaSC 基因特征进一步支持了这种表型。最后,我们的生化研究表明,Elf5 的缺失导致 Notch 信号通路的过度激活,这可能部分构成了 Elf5 缺失的乳腺上皮细胞中改变的细胞谱系决定的潜在分子机制。