Prox1 promotes lineage-specific expression of fibroblast growth factor (FGF) receptor-3 in lymphatic endothelium: A role for FGF signaling in lymphangiogenesis
Prox1 promotes lineage-specific expression of fibroblast growth factor (FGF) receptor-3 in lymphatic endothelium: A role for FGF signaling in lymphangiogenesis
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DOI：
10.1091/mbc.e05-04-0368
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发表时间：
2006-02-01
影响因子：
3.3
通讯作者：
Hong, YK
中科院分区：
文献类型：
--
作者：
Shin, JW;Min, M;Hong, YK
成纤维细胞生长因子在血管生成中起重要作用，但其在淋巴管生成中的功能仍知之甚少。同源域转录因子Prox 1通过指定淋巴管内皮细胞（LEC）的命运对淋巴系统的发育至关重要。在这里，我们确定成纤维细胞生长因子（FGF）受体（FGFR）-3作为一种新的Prox 1靶基因。血管内皮细胞中Prox 1的异位过表达上调FGFR-3。Prox 1诱导IIIc亚型的表达，我们还发现IIIc亚型是LEC中表达的FGFR-3的主要亚型。这种转录激活是由Prox 1与FGFR-3启动子中新鉴定的Prox 1反应元件直接结合介导的。一致的是，FGFR-3在胚胎发生期间在Prox 1阳性的新形成的淋巴管中上调，并且在整个发育过程中维持其细胞特异性表达。我们还发现，FGF-1和FGF-2促进增殖，迁移，和不参与血管内皮细胞生长因子受体3的培养LEC的生存。我们发现FGF-2与LEC上的低亲和力和高亲和力受体结合，并被有效地内化和加工。此外，使用小干扰RNA功能性抑制FGFR-3抑制LEC增殖。总之，这些结果表明FGFR-3是淋巴细胞命运指定过程中Prox 1的初始靶点，并且FGF信号传导可能在淋巴管发育中发挥重要作用。
Fibroblast growth factors play important roles in angiogenesis, but their functions in lymphangiogenesis remain poorly understood. The homeodomain transcription factor Prox1 is essential for development of the lymphatic system by specifying lymphatic endothelial cell (LEC) fate. Here, we identify fibroblast growth factor (FGF) receptor (FGFR)-3 as a novel Prox1 target gene. Ectopic overexpression of Prox1 in blood vascular endothelial cells up-regulates FGFR-3. Prox1 induces the expression of the IIIc isoform, which we also found to be the major isoform of FGFR-3 expressed in LECs. This transcriptional activation is mediated by a direct binding of Prox1 to newly identified Prox1-response elements in the FGFR-3 promoter. Consistently, FGFR-3 is up-regulated in Prox1-positive newly formed lymphatic vessels during embryogenesis and its lymphatic-specific expression is maintained throughout development. We also found that FGF-1 and FGF-2 promote proliferation, migration, and survival of cultured LECs without involvement of vascular endothelial cell growth factor receptor-3. We show that FGF-2 binds to low- and high-affinity receptors on LECs and is efficiently internalized and processed. Moreover, functional inhibition of FGFR-3 using small interfering RNA represses LEC proliferation. Together, these results indicate that FGFR-3 is an initial target of Prox1 during the lymphatic cell fate specification and that FGF signaling may play an important role in lymphatic vessel development.