Forkhead transcription factors regulate expression of the chemokine receptor CXCR4 in endothelial cells and CXCL12-induced cell migration

Abstract

Foxc1 and Foxc2 transcription factors are required for vascular development. However, the molecular mechanisms by which Foxc1 and Foxc2 control angiogenesis, the growth of new blood vessels from pre-existing vessels and capillaries, remain unknown. CXC chemokine ligand 12 (CXCL12) and its receptor, CXCR4, are critical for the process of angiogenesis, including the migration and tube formation of endothelial cells. Here we show that Foxc1 and Foxc2 directly induce CXCR4 expression by activating its promoter in endothelial cells. Furthermore, Foxc1-deficient endothelial cells show a significant reduction in CXCR4 expression as well as CXCL12-stimulated migration. Taken together, these results provide novel evidence that Foxc transcription factors are important regulators of the chemotactic motility of endothelial cells through the induction of CXCR4 expression.

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

“…Mice with an endothelial cell-specific (EC-specific) Foxc1 mutation (EC-Foxc1-KO) (47,48), generated by crossing Foxc1 fl mice (34) with Tie2-Cre mice (49), were also examined for defects in mesenteric lymphatic valves, as shown in the deletion of the integrin-α9 gene in the developing lymphatic valves (50) using Tie2-Cre mice (51). According to recent descriptions of the stages of lymphatic valve development (22,44,52), the proportion of mature lymphatic valves that had formed a characteristic V-shape at P7 was significantly lower in the EC-Foxc1-KO mice than in their littermate controls (Supplemental Figure 7, F-K).…”

The transcription factor Foxc1 is necessary for Ihh–Gli2-regulated endochondral ossification

“…For example, during sternal development, bilateral sternal cartilage bars migrate towards the midline and fuse to form the sternum; this is followed by chondrocyte hypertrophy and ossification 55 , suggesting a critical role for cell migration during the development of the sternum. Interestingly, Foxc1 is expressed in the sternum primordium of the E12.5 mouse embryo 45 and several reports indicate that it is involved in the migration of various types of cells, including germ 56 , endothelial 57 and breast cancer cells 58 . These data suggest that Foxc1-dependent cell migration also contributes to skeletal development.…”

Biomarkers for epithelial-mesenchymal transitions

“…During embryonic development, FOXC2 is widely expressed and is required for angiogenesis, musculogenesis, and organogenesis of the kidney, heart, and urinary tract (112,113). Postnatally, expression of FOXC2 is normally restricted to adipocytes (114).…”