FOXO1 regulates developmental lymphangiogenesis by upregulating CXCR4 in the mouse-tail dermis
FOXO1 regulates developmental lymphangiogenesis by upregulating CXCR4 in the mouse-tail dermis
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DOI：
10.1242/dev.181545
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发表时间：
2020-01-01
期刊：
影响因子：
4.6
通讯作者：
Furuyama, Tatsuo
中科院分区：
文献类型：
--
作者：
Niimi, Kenta;Kohara, Misaki;Furuyama, Tatsuo
淋巴管生成在胎儿的正常发育和出生后的生长发育中起重要作用。然而，其分子调控机制仍不清楚。在这里，我们研究了叉头盒蛋白O 1（FOXO 1）转录因子，一种已知的血管生成因子，在发展中的皮肤淋巴管生成内皮细胞特异性FOXO 1缺陷小鼠的功能。FOXO 1缺陷小鼠表现为淋巴管断开和扩张，伴有毛细淋巴管增殖增加和凋亡减少。对FOXO 1缺陷小鼠体内表型原因的全面DNA微阵列分析显示，编码C-X-C趋化因子受体4（CXCR 4）的基因在FOXO 1缺陷的原代淋巴管内皮细胞（LEC）中下调最剧烈。CXCR 4在野生型小鼠的真皮毛细淋巴管中表达，但在FOXO 1缺陷的真皮毛细淋巴管中不表达。此外，FOXO 1抑制损害了向外源性CXCR 4配体C-X-C趋化因子配体12（CXCL 12）的迁移，并协调了LEC的增殖。这些结果表明，FOXO 1通过促进LEC向CXCL 12迁移并调节其增殖活性，在正常发育的淋巴管生成中起重要作用。这项研究提供了有价值的见解，发展淋巴管生成的分子机制。
Lymphangiogenesis plays important roles in normal fetal development and postnatal growth. However, its molecular regulation remains unclear. Here, we have examined the function of forkhead box protein O1 (FOXO1) transcription factor, a known angiogenic factor, in developmental dermal lymphangiogenesis using endothelial cell-specific FOXO1-deficient mice. FOXO1deficient mice showed disconnected and dilated lymphatic vessels accompanied with increased proliferation and decreased apoptosis in the lymphatic capillaries. Comprehensive DNA microarray analysis of the causes of in vivo phenotypes in FOXO1-deficient mice revealed that the gene encoding C-X-C chemokine receptor 4 (CXCR4) was the most drastically downregulated in FOXO1-deficient primary lymphatic endothelial cells (LECs). CXCR4 was expressed in developing dermal lymphatic capillaries in wild-type mice but not in FOXO1-deficient dermal lymphatic capillaries. Furthermore, FOXO1 suppression impaired migration toward the exogenous CXCR4 ligand, C-X-C chemokine ligand 12 (CXCL12), and coordinated proliferation in LECs. These results suggest that FOXO1 serves an essential role in normal developmental lymphangiogenesis by promoting LEC migration toward CXCL12 and by regulating their proliferative activity. This study provides valuable insights into the molecular mechanisms underlying developmental lymphangiogenesis.