Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation

Anees Fatima, Ying Wang, Yutaka Uchida, Pieter Norden, Ting Liu, Austin Culver, William H. Dietz, Ford Culver, Meredith Millay, Yoh Suke Mukouyama, Tsutomu Kume*

*Corresponding author for this work

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

The lymphatic vasculature is essential for maintaining interstitial fluid homeostasis, and dysfunctional lymphangiogenesis contributes to various pathological processes, including inflammatory disease and tumor metastasis. Mutations in FOXC2 are dominantly associated with late-onset lymphedema; however, the precise role of FOXC2 and a closely related factor, FOXC1, in the lymphatic system remains largely unknown. Here we identified a molecular cascade by which FOXC1 and FOXC2 regulate ERK signaling in lymphatic vessel growth. In mice, lymphatic endothelial cell-specific (LEC-specific) deletion of Foxc1, Foxc2, or both resulted in increased LEC proliferation, enlarged lymphatic vessels, and abnormal lymphatic vessel morphogenesis. Compared with LECs from control animals, LECs from mice lacking both Foxc1 and Foxc2 exhibited aberrant expression of Ras regulators, and embryos with LEC-specific deletion of Foxc1 and Foxc2, alone or in combination, exhibited ERK hyperactivation. Pharmacological ERK inhibition in utero abolished the abnormally enlarged lymphatic vessels in FOXC-deficient embryos. Together, these results identify FOXC1 and FOXC2 as essential regulators of lymphangiogenesis and indicate a new potential mechanistic basis for lymphatic-associated diseases.

Original languageEnglish (US)
Pages (from-to)2437-2451
Number of pages15
JournalJournal of Clinical Investigation
Volume126
Issue number7
DOIs
StatePublished - Jul 1 2016

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fatima, A., Wang, Y., Uchida, Y., Norden, P., Liu, T., Culver, A., Dietz, W. H., Culver, F., Millay, M., Mukouyama, Y. S., & Kume, T. (2016). Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation. Journal of Clinical Investigation, 126(7), 2437-2451. https://doi.org/10.1172/JCI80465