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

doi:10.1172/JCI80465

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

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

67 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 language	English (US)
Pages (from-to)	2437-2451
Number of pages	15
Journal	Journal of Clinical Investigation
Volume	126
Issue number	7
DOIs	https://doi.org/10.1172/JCI80465
State	Published - Jul 1 2016

Funding

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).

ASJC Scopus subject areas

General Medicine

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@article{7bf1fd5e9fea491d980f4bbee118292f,

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.",

author = "Anees Fatima and Ying Wang and Yutaka Uchida and Pieter Norden and Ting Liu and Austin Culver and Dietz, {William H.} and Ford Culver and Meredith Millay and Mukouyama, {Yoh Suke} and Tsutomu Kume",

note = "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).",

year = "2016",

month = jul,

day = "1",

doi = "10.1172/JCI80465",

language = "English (US)",

volume = "126",

pages = "2437--2451",

journal = "Journal of Clinical Investigation",

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publisher = "The American Society for Clinical Investigation",

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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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DO - 10.1172/JCI80465

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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 -

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

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