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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Gene targeting of VEGF-A in thymus epithelium disrupts thymus blood vessel architecture
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Gene targeting of VEGF-A in thymus epithelium disrupts thymus blood vessel architecture

机译：胸腺上皮中VEGF-A的基因靶向破坏了胸腺血管结构

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摘要

The thymus harbors an organ-typical dense network of branching and anastomosing blood vessels. To address the molecular basis for morphogenesis of this thymus-specific vascular pattern, we have inactivated a key vascular growth factor, VEGF-A, in thymus epithelial cells (TECs). Both Vegf-A alleles were deleted in TECs by a complementation strategy termed nude mouse [mutated in the transcription factor Foxn1 (forkhead box N1)] blastocyst complementation. Injection of Foxn1~(+/+) ES cells into Foxn1~(nuu) blasto-cysts reconstituted a functional thymus. By dissecting thymus stromal cell subsets, we have defined, in addition to medullary TECs (mTECs) and cortical TECs (cTECs), another prominent stromal cell subset designated cortical mesenchymal cells (cMes). In chi-meric thymi, mTECs and cTECs but not cMes were exclusively ES cell-derived. According to this distinct origin, the Vegf-A gene was deleted in mTECs and cTECs, whereas cMes still expressed Vegf-A. This genetic mosaic was associated with hypovascularization and disruption of the organ-typical network of vascular arcades. Thus, vascular growth factor production by TECs is required for normal thymus vascular architecture. These experiments provide insights into Foxn1-dependent and Foxn1-independent stromal cell development and demonstrate the value of this chimeric approach to analyzing gene function in thymus epithelium.
机译：胸腺具有分支和吻合血管的器官典型密集网络。为了解决这种胸腺特异性血管模式的形态发生的分子基础，我们已在胸腺上皮细胞（TECs）中灭活了关键的血管生长因子VEGF-A。这两个Vegf-A等位基因在TECs中被称为裸鼠[突变为转录因子Foxn1（前额框N1）突变]胚泡互补的互补策略删除。将Foxn1〜（+ / +）ES细胞注射到Foxn1〜（nu / nu）胚泡中，重建了功能性胸腺。通过解剖胸腺基质细胞亚群，我们不仅定义了髓质TEC（mTECs）和皮质TEC（cTECs），还定义了另一个显着的基质细胞亚群，称为皮质间质细胞（cMes）。在嵌合胸腺中，mTECs和cTECs而非ESMe完全是ES细胞衍生的。根据这一独特的起源，Vegf-A基因在mTECs和cTECs中被删除，而cMes仍表达Vegf-A。这种遗传镶嵌与血管减少和血管拱门的器官典型网络的破坏有关。因此，正常胸腺血管结构需要TECs产生血管生长因子。这些实验提供了对Foxn1依赖和不依赖Foxn1的基质细胞发育的见解，并证明了这种嵌合方法对分析胸腺上皮基因功能的价值。

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