Combinatorial effects of Flk1 and Tal1 on vascular and hematopoietic development in the mouse
Combinatorial effects of Flk1 and Tal1 on vascular and hematopoietic development in the mouse
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DOI：
10.1101/gad.1049803
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发表时间：
2003-02-01
影响因子：
10.5
通讯作者：
Rossant, J
中科院分区：
文献类型：
--
作者：
Ema, M;Faloon, P;Rossant, J
VEGF 受体 VEGFR2、Flk-1 或 Kdr 的小鼠胚胎突变体无法形成内皮细胞和造血细胞，这表明可能在两个谱系的共同祖细胞中发挥作用。转录因子 Tall (Scl) 在 Flk1(-/-) 胚胎中不表达，这与 Flk1 通路中的下游作用一致。我们测试了 Flk1 启动子下 Tall 的表达是否足以挽救 Flk1 突变体中内皮细胞和造血细胞的损失。在体内仅观察到造血和内皮发育的部分恢复。然而，Flk1(-/Tal1)胚胎干(ES)细胞能够在体外以相当于Flk1(+/-)杂合子的水平形成集落。在 Flk1(+/-) 小鼠胚胎或 ES 细胞中，Flk1 启动子下的 Tall 异位表达不会引起明显的病理，但会增加母细胞集落形成细胞 (BL-CFC) 的数量并增强其造血潜力。这些单细胞衍生的 BL-CFC 还在体外产生平滑肌细胞。在此测定中，Tall 表达增加抑制平滑肌分化，而 Tall 表达缺失则促进平滑肌形成。我们提出了一个模型，其中 Flk1 和 Tall 的组合作用可调节造血、内皮和平滑肌谱系早期发育中的细胞命运选择。
Mouse embryos mutant for the VEGF receptor, VEGFR2, Flk-1, or Kdr, fail to form both endothelial and hematopoietic cells, suggesting a possible role in a common progenitor to both lineages. The transcription factor Tall (Scl), is not expressed in Flk1(-/-) embryos, consistent with a downstream role in the Flk1 pathway. We tested whether expression of Tall under the Flk1 promoter was sufficient to rescue the loss of endothelial and hematopoietic cells in Flk1 mutants. Only partial rescue of hematopoiesis and endothelial development was observed in vivo. However, Flk1(-/Tal1) embryonic stem (ES) cells were capable of blast colony formation in vitro at levels equivalent to Flk1(+/-) heterozygotes. Ectopic expression of Tall under the Flk1 promoter in Flk1(+/-) mouse embryos or ES cells caused no obvious pathology but increased the number of blast colony forming cells (BL-CFCs) and enhanced their hematopoietic potential. These single-cell-derived BL-CFCs also produced smooth muscle cells in vitro. Increased Tall expression inhibited smooth muscle differentiation in this assay, whereas loss of Tall promoted smooth muscle formation. We propose a model in which the combinatorial effects of Flk1 and Tall act to regulate cell fate choice in early development into hematopoietic, endothelial, and smooth muscle lineages.