Cancer Research UK Stem Cell Research Group, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
Development. 2012 May;139(9):1587-98. doi: 10.1242/dev.071282.
At early stages of vertebrate ontogeny, blood and endothelial cells develop from a common mesodermal progenitor, the haemangioblast. Upon haematopoietic commitment, the haemangioblast generates blood precursors through populations of endothelial cells with haemogenic properties. Although several transcription factors have been implicated in haemangioblast differentiation, the precise mechanisms governing cell fate decisions towards the generation of haemogenic endothelium precursors remain largely unknown. Under defined conditions, embryonic stem (ES) cells can be differentiated into haemangioblast-like progenitors that faithfully recapitulate early embryonic haematopoiesis. Here, we made use of mouse ES cells as a model system to understand the role of SOX7, a member of a large family of transcription factors involved in a wide range of developmental processes. During haemangioblast differentiation, SOX7 is expressed in haemogenic endothelium cells and is downregulated in nascent blood precursors. Gain-of-function assays revealed that the enforced expression of Sox7 in haemangioblast-derived blast colonies blocks further differentiation and sustains the expression of endothelial markers. Thus, to explore the transcriptional activity of SOX7, we focused on the endothelial-specific adhesion molecule VE-cadherin. Similar to SOX7, VE-cadherin is expressed in haemogenic endothelium and is downregulated during blood cell formation. We show that SOX7 binds and activates the promoter of VE-cadherin, demonstrating that this gene is a novel downstream transcriptional target of SOX7. Altogether, our findings suggest that SOX7 is involved in the transcriptional regulation of genes expressed in the haemogenic endothelium and provide new clues to decipher the molecular pathways that drive early embryonic haematopoiesis.
在脊椎动物胚胎发生的早期阶段，血液和内皮细胞由共同的中胚层祖细胞——成血管细胞发育而来。在造血作用下，成血管细胞通过具有造血特性的内皮细胞群体产生血液前体。尽管已经有几个转录因子被牵连到成血管细胞的分化中，但控制向造血内皮前体细胞生成的细胞命运决定的确切机制在很大程度上仍然未知。在特定条件下，胚胎干细胞（ES 细胞）可以分化为成血管细胞样祖细胞，这些祖细胞忠实地再现了早期胚胎造血。在这里，我们利用小鼠 ES 细胞作为模型系统来理解 SOX7 的作用，SOX7 是一个涉及广泛发育过程的转录因子大家族的成员。在成血管细胞分化过程中，SOX7 在造血内皮细胞中表达，并在新出现的血液前体中下调。功能获得性测定显示，在成血管细胞衍生的胚集落中强制表达 Sox7 会阻止进一步分化，并维持内皮标记物的表达。因此，为了探索 SOX7 的转录活性，我们专注于血管特异性粘附分子 VE-cadherin。与 SOX7 相似，VE-cadherin 在造血内皮细胞中表达，并在血细胞形成过程中下调。我们表明 SOX7 结合并激活 VE-cadherin 的启动子，表明该基因是 SOX7 的一个新的下游转录靶标。总之，我们的研究结果表明 SOX7 参与了造血内皮细胞中表达的基因的转录调控，并为解析驱动早期胚胎造血的分子途径提供了新的线索。
