Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155 Gaetbeol-ro, Yeonsu-gu, Incheon, 21999, Republic of Korea.
Department of Physiology and Functional Genomics, College of Medicine, University of Florida, 1600 SW Archer Road, Room CG-20B, Gainesville, FL, USA.
Angiogenesis. 2020 Aug;23(3):339-355. doi: 10.1007/s10456-020-09713-1. Epub 2020 Feb 28.
TMEM100 is identified as a downstream gene of bone morphogenetic protein 9 (BMP9) signaling via activin receptor-like kinase 1 (ALK1), which is known to participate in lymphangiogenesis as well as angiogenesis. TMEM100 has been shown to be important for blood vessel formation and maintenance, but its role in the development of lymphatic vasculature remains unknown. The objective is to investigate the role of TMEM100 in development of the lymphatic system.
Global Tmem100 gene deletion was induced by tamoxifen on 10.5 days post-coitus. Tmem100-inducible knockout (iKO) embryos in embryonic days (E)14.5-16.5 exhibited edema and blood-filled enlarged lymphatics with misconnections between veins and lymphatic vessels. For a reciprocal approach, we have generated a novel mouse line in which TMEM100 overexpression (OE) can be induced in endothelial cells by intercrossing with Tie2-Cre driver. TMEM100-OE embryos at E12.5-14.5 exhibited edema with small size and number of lymphatic vessels, the exact opposite phenotypes of Tmem100-iKOs. In Tmem100-iKO embryos, the number of progenitors of lymphatic endothelial cells (LECs) in the cardinal vein was increased, while it was decreased in TMEM100-OE embryos. The activity of NOTCH signaling, which limits the number of progenitors of LECs in the cardinal vein, was decreased in Tmem100-iKO embryos, whereas it was increased in TMEM100-OE embryos.
TMEM100 plays an important role in the specification of LECs in the cardinal veins, at least in part, by regulating the NOTCH signaling.
TMEM100 是骨形态发生蛋白 9（BMP9）信号的下游基因，通过激活素受体样激酶 1（ALK1）识别，其已知参与淋巴管生成和血管生成。TMEM100 已被证明对血管形成和维持很重要，但它在淋巴管发育中的作用尚不清楚。本研究旨在探讨 TMEM100 在淋巴管系统发育中的作用。
通过在交配后 10.5 天用他莫昔芬诱导全局 Tmem100 基因缺失。在胚胎第 14.5-16.5 天，Tmem100 诱导型敲除（iKO）胚胎出现水肿和充满血液的增大淋巴管，静脉和淋巴管之间存在错误连接。为了进行反向研究，我们通过与 Tie2-Cre 驱动子杂交，生成了一种新的小鼠品系，内皮细胞中可以诱导 TMEM100 过表达（OE）。在 E12.5-14.5 天，TMEM100-OE 胚胎出现水肿，体积小，淋巴管数量少，与 Tmem100-iKO 胚胎的表型完全相反。在 Tmem100-iKO 胚胎中，心静脉中淋巴管内皮细胞（LEC）祖细胞的数量增加，而在 TMEM100-OE 胚胎中则减少。NOTCH 信号的活性，限制了心静脉中 LEC 祖细胞的数量，在 Tmem100-iKO 胚胎中降低，而在 TMEM100-OE 胚胎中增加。
TMEM100 通过调节 NOTCH 信号，在至少部分程度上，在心静脉中 LEC 的特化中发挥重要作用。
