Transcription factor FOXP2 is a flow-induced regulator of collecting lymphatic vessels

EMBO J. 2021 Jun 15;40(12):e107192. doi: 10.15252/embj.2020107192. Epub 2021 May 2.


The lymphatic system is composed of a hierarchical network of fluid absorbing lymphatic capillaries and transporting collecting vessels. Despite distinct functions and morphologies, molecular mechanisms that regulate the identity of the different vessel types are poorly understood. Through transcriptional analysis of murine dermal lymphatic endothelial cells (LECs), we identified Foxp2, a member of the FOXP family of transcription factors implicated in speech development, as a collecting vessel signature gene. FOXP2 expression was induced after initiation of lymph flow in vivo and upon shear stress on primary LECs in vitro. Loss of FOXC2, the major flow-responsive transcriptional regulator of lymphatic valve formation, abolished FOXP2 induction in vitro and in vivo. Genetic deletion of Foxp2 in mice using the endothelial-specific Tie2-Cre or the tamoxifen-inducible LEC-specific Prox1-CreERT2 line resulted in enlarged collecting vessels and defective valves characterized by loss of NFATc1 activity. Our results identify FOXP2 as a new flow-induced transcriptional regulator of collecting lymphatic vessel morphogenesis and highlight the existence of unique transcription factor codes in the establishment of vessel-type-specific endothelial cell identities.

Keywords: lymphatic vessel; shear stress; valve.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Endothelial Cells / metabolism
  • Female
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Profiling
  • Humans
  • Lymphangiogenesis*
  • Lymphatic Vessels*
  • Male
  • Mice, Transgenic
  • Morphogenesis
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Stress, Mechanical


  • Forkhead Transcription Factors
  • Foxp2 protein, mouse
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • Repressor Proteins

Associated data

  • GEO/GSE159842