FOXO1 regulates developmental lymphangiogenesis by upregulating CXCR4 in the mouse-tail dermis

Kenta Niimi, Misaki Kohara, Eriko Sedoh, Moe Fukumoto, Satoshi Shibata, Toshinori Sawano, Fumi Tashiro, Satsuki Miyazaki, Yoshiaki Kubota, Jun Ichi Miyazaki, Shinobu Inagaki, Tatsuo Furuyama

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


Lymphangiogenesis plays important roles in normal fetal development and postnatal growth. However, its molecular regulation remains unclear. Here, we have examined the function of forkhead box protein O1 (FOXO1) transcription factor, a known angiogenic factor, in developmental dermal lymphangiogenesis using endothelial cell-specific FOXO1-deficient mice. FOXO1- deficient mice showed disconnected and dilated lymphatic vessels accompanied with increased proliferation and decreased apoptosis in the lymphatic capillaries. Comprehensive DNA microarray analysis of the causes of in vivo phenotypes in FOXO1-deficient mice revealed that the gene encoding C-X-C chemokine receptor 4 (CXCR4) was the most drastically downregulated in FOXO1-deficient primary lymphatic endothelial cells (LECs). CXCR4 was expressed in developing dermal lymphatic capillaries in wild-type mice but not in FOXO1-deficient dermal lymphatic capillaries. Furthermore, FOXO1 suppression impaired migration toward the exogenous CXCR4 ligand, C-X-C chemokine ligand 12 (CXCL12), and coordinated proliferation in LECs. These results suggest that FOXO1 serves an essential role in normal developmental lymphangiogenesis by promoting LEC migration toward CXCL12 and by regulating their proliferative activity. This study provides valuable insights into the molecular mechanisms underlying developmental lymphangiogenesis.

Original languageEnglish
Article numberdev181545
JournalDevelopment (Cambridge)
Issue number2
Publication statusPublished - 2020


  • C-X-C chemokine ligand 12 (CXCL-12)
  • C-X-C chemokine receptor type 4 (CXCR-4)
  • Chemokine
  • FOXO
  • Lymphangiogenesis
  • Tail dermis

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology


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