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TMEM100 is a key factor for specification of lymphatic endothelial progenitors

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Abstract

Background

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.

Methods and results

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.

Conclusion

TMEM100 plays an important role in the specification of LECs in the cardinal veins, at least in part, by regulating the NOTCH signaling.

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Acknowledgements

We thank C. Song, K.S. Ko, and S. Lee for technical assistance in animal experiments. We also thank Dr. T. Makinen (Uppsala University, Uppsala, Sweden) for providing Prox1-CreER mice. This work was supported by Barrow Neurological Foundation, Leducq Foundation (ATTRACT), Department of Defense (PR161205), and NIH (HL128525) to S.P.O., and Korea Mouse Phenoty** Project [Grant Number NRF-2014M3A9D5A01073528] of the Ministry of Science and ICT through the National Research Foundation (NRF) to Y.J.L., in part by NRF Grant funded by the Ministry of Science and ICT [Grant Number NRF-2017R1A2B4003322] to Y.J.L.

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  1. Eun-Hye Moon and Yong Hwan Kim have contributed equally to this work.

Authors and Affiliations

  1. Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155 Gaetbeol-ro, Yeonsu-gu, Incheon, 21999, Republic of Korea

    Eun-Hye Moon, Phuong-Nhung Vu & Young Jae Lee

  2. Department of Physiology and Functional Genomics, College of Medicine, University of Florida, 1600 SW Archer Road, Room CG-20B, Gainesville, FL, USA

    Yong Hwan Kim & S. Paul Oh

  3. Department of Neurobiology, Barrow Aneurysm and AVM Research Center, Barrow Neurological Institute, 350 W Thomas Rd, Phoenix, AZ, 85013, USA

    Yong Hwan Kim & S. Paul Oh

  4. Department of Stem Cell & Regenerative Biotechnology, Konkuk University, Seoul, 05029, Republic of Korea

    Hyun** Yoo & Kwonho Hong

  5. Department of Biochemistry, College of Medicine, Gachon University, Incheon, Republic of Korea

    Young Jae Lee

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EHM, YHK, YJL, and SPO contributed to the study conception and design. Material preparation, data collection, and analysis were performed by all authors. The manuscript was written by EHM, YHK, YJL, and SPO and all authors commented on the manuscript. All authors read and approved the final manuscript.

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Moon, EH., Kim, Y.H., Vu, PN. et al. TMEM100 is a key factor for specification of lymphatic endothelial progenitors. Angiogenesis 23, 339–355 (2020). https://doi.org/10.1007/s10456-020-09713-1

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