title: Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation.
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.
authors.forename: Anees
authors.initials: A
authors.lastname: Fatima
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Uchida
authors.forename: Pieter
authors.initials: P
authors.lastname: Norden
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: Austin
authors.initials: A
authors.lastname: Culver
authors.forename: William H
authors.initials: WH
authors.lastname: Dietz
authors.forename: Ford
authors.initials: F
authors.lastname: Culver
authors.forename: Meredith
authors.initials: M
authors.lastname: Millay
authors.forename: Yoh-Suke
authors.initials: YS
authors.lastname: Mukouyama
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kume
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007249:Inflammation; D042583:Lymphangiogenesis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012867:Skin / Q000378:metabolism
chemical_list: C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse; C082078:mesenchyme fork head 1 protein; D048049:Extracellular Signal-Regulated MAP Kinases