Dahl Richard, Walsh Jonathan C, Lancki David, Laslo Peter, Iyer Sangeeta R, Singh Harinder, Simon M Celeste
Howard Hughes Medical Institute, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Nat Immunol. 2003 Oct;4(10):1029-36. doi: 10.1038/ni973. Epub 2003 Sep 7.
Hematopoietic transcription factors are essential for specifying cell fates; however, the function of cytokines in such developmental decisions is unresolved. We demonstrate here that haploinsufficiency for the gene encoding the transcription factor PU.1 partially suppresses the neutropenia of mice deficient in granulocyte colony-stimulating factor. This suppression was due to an increase in granulocytic progenitors and a diminution of monocytic progenitors. With (PU.1+/-) ES cells as well as (PU.1-/-) hematopoietic progenitors, we show that higher expression of PU.1 is needed for macrophage than for neutrophil development. In a (PU.1-/-) progenitor cell line, in which graded activity of PU.1 regulates neutrophil versus macrophage development, granulocyte colony-stimulating factor signaling supported the neutrophil cell fate by increasing expression of the neutrophil transcription factor C/EBPalpha in relation to expression of PU.1. Collectively, these results indicate that cytokines can promote cell fate decisions by altering the relative concentrations of lineage-determining transcriptional regulators.
造血转录因子对于确定细胞命运至关重要；然而，细胞因子在这种发育决定中的功能尚未明确。我们在此证明，编码转录因子PU.1的基因单倍剂量不足可部分抑制粒细胞集落刺激因子缺陷小鼠的中性粒细胞减少症。这种抑制是由于粒细胞祖细胞增加和单核细胞祖细胞减少所致。利用（PU.1+/-）胚胎干细胞以及（PU.1-/-）造血祖细胞，我们发现巨噬细胞发育比中性粒细胞发育需要更高水平的PU.1表达。在一种（PU.1-/-）祖细胞系中，PU.1的分级活性调节中性粒细胞与巨噬细胞的发育，粒细胞集落刺激因子信号通过增加中性粒细胞转录因子C/EBPα相对于PU.1表达的水平来支持中性粒细胞的细胞命运。总的来说，这些结果表明细胞因子可通过改变决定谱系的转录调节因子的相对浓度来促进细胞命运的决定。
