Blood and lymphatic systems are segregated by the FLCN tumor suppressor

Ikue Tai-Nagara, Yukiko Hasumi, Dai Kusumoto, Hisashi Hasumi, Keisuke Okabe, Tomofumi Ando, Fumio Matsuzaki, Fumiko Itoh, Hideyuki Saya, Chang Liu, Wenling Li, Yoh suke Mukouyama, W. Marston Linehan, Xinyi Liu, Masanori Hirashima, Yutaka Suzuki, Shintaro Funasaki, Yorifumi Satou, Mitsuko Furuya, Masaya BabaYoshiaki Kubota

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)


Blood and lymphatic vessels structurally bear a strong resemblance but never share a lumen, thus maintaining their distinct functions. Although lymphatic vessels initially arise from embryonic veins, the molecular mechanism that maintains separation of these two systems has not been elucidated. Here, we show that genetic deficiency of Folliculin, a tumor suppressor, leads to misconnection of blood and lymphatic vessels in mice and humans. Absence of Folliculin results in the appearance of lymphatic-biased venous endothelial cells caused by ectopic expression of Prox1, a master transcription factor for lymphatic specification. Mechanistically, this phenotype is ascribed to nuclear translocation of the basic helix-loop-helix transcription factor Transcription Factor E3 (TFE3), binding to a regulatory element of Prox1, thereby enhancing its venous expression. Overall, these data demonstrate that Folliculin acts as a gatekeeper that maintains separation of blood and lymphatic vessels by limiting the plasticity of committed endothelial cells.

Original languageEnglish
Article number6314
JournalNature communications
Issue number1
Publication statusPublished - 12-2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General
  • General Physics and Astronomy


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