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

Area of Science:

• Vascular biology
• Molecular genetics
• Developmental biology

Background:

• The lymphatic vasculature is vital for fluid balance and preventing disease.
• Dysfunctional lymphangiogenesis is linked to inflammatory diseases and cancer spread.
• FOXC2 mutations cause lymphedema, but FOXC1 and FOXC2 roles in lymphatics are unclear.

Purpose of the Study:

• To elucidate the roles of FOXC1 and FOXC2 in lymphatic vessel development.
• To identify the molecular mechanisms by which FOXC1 and FOXC2 regulate lymphangiogenesis.
• To explore the link between FOXC1/FOXC2, ERK signaling, and lymphatic abnormalities.

Main Methods:

• Generated mice with lymphatic endothelial cell-specific deletion of Foxc1, Foxc2, or both.
• Analyzed lymphatic vessel morphology and LEC proliferation in knockout mice.
• Investigated gene expression of Ras regulators and ERK signaling pathway activity.
• Utilized pharmacological ERK inhibition in developing embryos.

Main Results:

• LEC-specific deletion of Foxc1 and/or Foxc2 caused enlarged lymphatic vessels and abnormal morphogenesis.
• LECs lacking both FOXC1 and FOXC2 showed altered Ras regulator expression.
• FOXC-deficient embryos exhibited ERK hyperactivation in lymphatic endothelial cells.
• In utero ERK inhibition normalized lymphatic vessel enlargement in FOXC-deficient embryos.

Conclusions:

• FOXC1 and FOXC2 are essential regulators of lymphangiogenesis.
• A molecular cascade involving FOXC1/FOXC2, Ras regulators, and ERK signaling controls lymphatic vessel growth.
• These findings provide a mechanistic basis for lymphatic disorders like lymphedema and potentially tumor metastasis.