TY - JOUR
T1 - Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation
AU - Fatima, Anees
AU - Wang, Ying
AU - Uchida, Yutaka
AU - Norden, Pieter
AU - Liu, Ting
AU - Culver, Austin
AU - Dietz, William H.
AU - Culver, Ford
AU - Millay, Meredith
AU - Mukouyama, Yoh Suke
AU - Kume, Tsutomu
N1 - Funding Information:
We thank Tatiana Petrova, Susan Quaggin, Olga Volpert, and Ordan Lehmann for critical reading of the manuscript. We thank Guillermo Oliver and Rong Wang for providing the Prox1-CreERT2 and Tie2-Cre mouse lines, respectively. We thank Yong K. Hong for providing human LECs. Immunofluorescence staining for p-ERK/PROX1 was performed at the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by National Cancer Institute (NCI) P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. This work was supported by the NIH (HL 126920 and EY019484 to T. Kume) and the American Heart Association (AHA-14POST20390029 to Y. Wang).
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI80465
DO - 10.1172/JCI80465
M3 - Article
C2 - 27214551
AN - SCOPUS:84978413844
SN - 0021-9738
VL - 126
SP - 2437
EP - 2451
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -