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YAP 和 TAZ 通过响应 VEGF-C 信号来维持发育中的淋巴管和淋巴静脉瓣膜中 PROX1 的表达。

YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling.

机构信息

Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA

Daegu Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.

出版信息

Development. 2020 Dec 13;147(23):dev195453. doi: 10.1242/dev.195453.

DOI:10.1242/dev.195453
PMID:33060128
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7758626/
Abstract

Lymphatic vasculature is an integral part of digestive, immune and circulatory systems. The homeobox transcription factor PROX1 is necessary for the development of lymphatic vessels, lymphatic valves (LVs) and lymphovenous valves (LVVs). We and others previously reported a feedback loop between PROX1 and vascular endothelial growth factor-C (VEGF-C) signaling. PROX1 promotes the expression of the VEGF-C receptor VEGFR3 in lymphatic endothelial cells (LECs). In turn, VEGF-C signaling maintains PROX1 expression in LECs. However, the mechanisms of PROX1/VEGF-C feedback loop remain poorly understood. Whether VEGF-C signaling is necessary for LV and LVV development is also unknown. Here, we report for the first time that VEGF-C signaling is necessary for valve morphogenesis. We have also discovered that the transcriptional co-activators YAP and TAZ are required to maintain PROX1 expression in LVs and LVVs in response to VEGF-C signaling. Deletion of and in the lymphatic vasculature of mouse embryos did not affect the formation of LVs or LVVs, but resulted in the degeneration of these structures. Our results have identified VEGF-C, YAP and TAZ as a crucial molecular pathway in valve development.

摘要

淋巴管系统是消化系统、免疫系统和循环系统的一个组成部分。同源盒转录因子 PROX1 对于淋巴管、淋巴瓣膜 (LV) 和淋巴静脉瓣膜 (LVV) 的发育是必需的。我们和其他人之前曾报道过 PROX1 和血管内皮生长因子-C (VEGF-C) 信号之间的反馈回路。PROX1 促进淋巴管内皮细胞 (LEC) 中 VEGF-C 受体 VEGFR3 的表达。反过来，VEGF-C 信号又维持 LEC 中 PROX1 的表达。然而，PROX1/VEGF-C 反馈回路的机制仍知之甚少。VEGF-C 信号对于 LV 和 LVV 的发育是否也是必需的，目前也不清楚。在这里，我们首次报道 VEGF-C 信号对于瓣膜形态发生是必需的。我们还发现，转录共激活因子 YAP 和 TAZ 对于响应 VEGF-C 信号在 LV 和 LVV 中维持 PROX1 的表达是必需的。在小鼠胚胎的淋巴管系统中缺失 和 不会影响 LV 或 LVV 的形成，但会导致这些结构退化。我们的结果已经确定 VEGF-C、YAP 和 TAZ 是瓣膜发育的关键分子途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/705e9b8fbe4c/develop-147-195453-g10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/a190c83e99c9/develop-147-195453-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/742d82810fb5/develop-147-195453-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/b21d0a97e963/develop-147-195453-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/b142897643d3/develop-147-195453-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/70d6e721330c/develop-147-195453-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/8096ad1e22b5/develop-147-195453-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/2d09c9c6bde5/develop-147-195453-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/f450ebb1c7ec/develop-147-195453-g8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/3c659d095395/develop-147-195453-g9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/705e9b8fbe4c/develop-147-195453-g10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/a190c83e99c9/develop-147-195453-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/742d82810fb5/develop-147-195453-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/b21d0a97e963/develop-147-195453-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/b142897643d3/develop-147-195453-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/70d6e721330c/develop-147-195453-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/8096ad1e22b5/develop-147-195453-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/2d09c9c6bde5/develop-147-195453-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/f450ebb1c7ec/develop-147-195453-g8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/3c659d095395/develop-147-195453-g9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5896/7758626/705e9b8fbe4c/develop-147-195453-g10.jpg

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