Blood and lymphatic systems are segregated by the FLCN tumor suppressor

Nat Commun. 2020 Dec 9;11(1):6314. doi: 10.1038/s41467-020-20156-6.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cell Nucleus / metabolism
  • Cell Plasticity*
  • Embryo, Mammalian
  • Endothelial Cells / metabolism
  • Endothelium, Lymphatic / cytology
  • Endothelium, Lymphatic / embryology
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / embryology
  • Female
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Lymphatic Vessels / cytology
  • Lymphatic Vessels / embryology*
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Proto-Oncogene Proteins / deficiency*
  • Proto-Oncogene Proteins / genetics
  • RNA Interference
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Veins / cytology
  • Veins / embryology*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Bhd protein, mouse
  • FLCN protein, human
  • Homeodomain Proteins
  • Proto-Oncogene Proteins
  • TFE3 protein, human
  • Tumor Suppressor Proteins
  • prospero-related homeobox 1 protein
  • Tcfe3 protein, mouse