Lohmann Felix, Bieker James J
Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, Box 1020, 1 Gustave Levy Place, New York, NY 10029, USA.
Development. 2008 Jun;135(12):2071-82. doi: 10.1242/dev.018200. Epub 2008 Apr 30.
The hierarchical progression of stem and progenitor cells to their more-committed progeny is mediated through cell-to-cell signaling pathways and intracellular transcription factor activity. However, the mechanisms that govern the genetic networks underlying lineage fate decisions and differentiation programs remain poorly understood. Here we show how integration of Bmp4 signaling and Gata factor activity controls the progression of hematopoiesis, as exemplified by the regulation of Eklf during establishment of the erythroid lineage. Utilizing transgenic reporter assays in differentiating mouse embryonic stem cells as well as in the murine fetal liver, we demonstrate that Eklf expression is initiated prior to erythroid commitment during hematopoiesis. Applying phylogenetic footprinting and in vivo binding studies in combination with newly developed loss-of-function technology in embryoid bodies, we find that Gata2 and Smad5 cooperate to induce Eklf in a progenitor population, followed by a switch to Gata1-controlled regulation of Eklf transcription upon erythroid commitment. This stage- and lineage-dependent control of Eklf expression defines a novel role for Eklf as a regulator of lineage fate decisions during hematopoiesis.
干细胞和祖细胞向其更定向的子代细胞的分级进展是通过细胞间信号通路和细胞内转录因子活性介导的。然而，控制谱系命运决定和分化程序背后的遗传网络的机制仍知之甚少。在这里，我们展示了Bmp4信号和Gata因子活性的整合如何控制造血过程的进展，以红细胞谱系建立过程中Eklf的调控为例。利用转基因报告分析在分化的小鼠胚胎干细胞以及小鼠胎肝中进行研究，我们证明在造血过程中，Eklf表达在红细胞定向之前就已启动。通过系统发育足迹分析和体内结合研究，并结合在胚状体中新开发的功能丧失技术，我们发现Gata2和Smad5在祖细胞群体中协同诱导Eklf，随后在红细胞定向后转变为Gata1对Eklf转录的调控。这种对Eklf表达的阶段和谱系依赖性控制定义了Eklf在造血过程中作为谱系命运决定调节因子的新作用。
