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Foxc2 Transcription Factor: a Novel Regulator of Lymphangiogenesis

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Foxc2 Transcription Factor: a Novel Regulator of Lymphangiogenesis 35 Lymphology 44 (2011) 35-41 FOXC2 TRANSCRIPTION FACTOR: A NOVEL REGULATOR OF LYMPHANGIOGENESIS X. Wu, N.-F. Liu Lymphology Center of Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, People’s Republic of China ABSTRACT life. Although embryonic vein endothelial cells sprout and incorporate to form primary Lymphangiogenesis is the critical process lymph sacs and primary lymphatic plexus (1), of forming new lymphatic vessels under subsequent processes of vascular remodeling physiological and pathological conditions and and maturation gives rise to a functional involves both molecular and morphological network of lymphatic vessels, including changes. Despite evidence that lymphangio- lymphatic capillaries responsible for absorp- genic factors, including vascular endothelial tion of interstitial fluid and collecting lymph growth factors (VEGFs) and Prox1, regulate vessels that transport the lymph back to the lymphangiogenesis, the molecular mechanisms blood circulation. While lymphangiogenesis underlying gene regulation in lymphatic vessel occurs normally in almost all tissues under remodeling and maturation are not fully physiological conditions (with the notable understood. Importantly, recent studies exceptions of the central nervous system, demonstrate that Forkhead transcription bone marrow, cartilage, cornea and factor FOXC2 controls later steps of lymphatic epidermis), elucidation of the mechanisms vascular development and is responsible for involved in pathological lymphangiogenesis establishing a collecting lymphatic vessel such as solid tumor metastasis, inflammation identity by regulating expression of down- and lymphedema is clearly of great impor- stream genes involved in lymphangiogenesis, tance. Recent work has discovered several including PDGF-ß, Delta-like 4 (Dll4) and regulators including the transcription factors angiopoietin (Ang)-2. Thus, FOXC2 is now Prox1 (2), VEGFR-3/ VEGF-C (3), Tie/Ang2 recognized as a novel regulator of lymphatic (4), and EphrinB2 (5), which contribute to vascular formation and remodeling. This early lymphangiogenesis. However, the later review summarizes current knowledge about steps of lymphatic vascular development the function of FOXC2 in lymphangiogenesis including the maturation of the primary and discusses prospects for future research in lymphatic plexus into functional collecting FOXC2-mediated pathological lymphangio- vessels and capillaries, remain largely genesis in lymphatic-related disease. unknown and need further investigation. Here we discuss the rapidly accumulating Keywords: FOXC2, remodeling and evidence that transcription factor FOXC2 is maturation, lymphangiogenesis. a key regulator during lymphatic remodeling and maturation. Lymphatic network formation is vital for embryonic development as well as postnatal Physiological Roles of FOXC2 during Permission granted for single print for individual use. Reproductiom not permitted without permission of Journal LYMPHOLOGY. 36 Development and in the Adult form lymphatic valves and increased mural cell investment of lymphatic capillaries in a FOXC2 is a member of the forkhead/ mouse model, indicating Foxc2’s role in winged-helix family of transcription factor remodeling and maturation of lymphatic genes that is located on the long (q) arm of vessels (19). Further investigations using chromosome 16 at position 24.1 (6). The gene, models of animal development showed that with a single exon which is highly GC rich, change in Foxc2 expression is the critical first encodes for a 2.2 Kb protein (7). Forkhead event of the maturation process of lymphatic box proteins are characterized by the vessels (18), configuring Foxc2 as an forkhead box, a DNA binding Motif with a important transcriptional regulator to control sequence of 80 to 100 amino acids (8). In expression of multiple genes in the process of humans, the FOX family of transcription lymphatic maturation. This conclusion is factors is present in various embryonic organs supported by the observation that Foxc2 and tissues during development and plays inhibited SMC coverage of initial lymphatic crucial roles in a variety of processes such as vessels through suppressing the expression of proliferation, differentiation and survival (9). PDGF-ß, a potent chemoattractant for FOXC2 protein, also known as forkhead- vSMCs, in lymphatic vessels (19,22). Notably, related protein FKHL14 (FKHL14), Foxc2 regulated the transcriptional network transcription factor FKH-14, or mesenchyme in this process in cooperation with nuclear forkhead protein (MFH1), belongs to the “C” factor of activated T cells (NFATc)-1 that has subfamily and is required for cardiovascular been found to control the morphogenesis of development (10) as well as the development cardiac valves (18,23). of the lungs (11), eyes (12), kidneys (13) and Interestingly, patients with Lymphedema- urinary tract (14). Recently, FOXC2 has been Distichiasis syndrome (LD) [Online shown to be involved in cancer angiogenesis Mendelian Inheritance in Man (OMIM)], a and metastasis (15) and is particularly disease caused by mutations in FOXC2, have implicated in cancer progression through its a similar phenotype to Foxc2 null (19) and induction of epithelial-to-mesenchymal haploinsufficient mice (20). So far, mutations transition (16). Moreover, suppression of in FOXC2 have been found to be the only FOXC2 expression using shRNA in a highly known cause of LD. Moreover, frameshift metastatic breast cancer model blocked mutations that involve a probable loss-of- metastatic ability (17), indicating FOXC2 function mechanism (24-26) were the might be another therapeutic target for predominant mutations, whereas nonsense cancer therapy. and missense mutations were rare (7,26,27). While genotype/phenotype correlation has Role of Foxc2 in Lymphatic Vascular not been clearly delineated, all mutations Development including frameshift and nonsense mutations that are responsible for LD truncate the Recently, Foxc2 has been shown to be protein, leading to FOXC2 haploinsufficiency implicated in lymphatic vascular develop- (24,26,28,29). Clinically, affected patients ment and disease (18,19). The fact that Foxc2 commonly have bilateral lymphedema of the is highly expressed in the developing lower limbs that usually develops around lymphatic vessels as well as lymphatic valves puberty and abnormal eyelashes (a double in adult mice raises the possibility that it row of eyelashes) (7). In addition to these serves a function in the development and specific signs of LD, other associated compli- maintenance of the lymphatic vasculature cations may include ptosis (31%), varicose (19-21). Moreover, loss of Foxc2 leads to veins (25%), congenital heart diseases (6.8- abnormal lymphatic patterning, failure to 10%), and cleft palate (4-10%). Scoliosis, Permission granted for single print for individual use. Reproductiom not permitted without permission of Journal LYMPHOLOGY. 37 renal anomalies, hydrocele, strabismus have roles in development of some organs (33-36), also been reported but are less common (26), Foxc1 has been shown to be absent in suggesting the phenotypic spectrum of LD lymphatics (21). These observations suggest could be variable. that Foxc2 regulates the maturation of Further investigation of the lymphedema- lymphatic vessels, whereas early lymphatic distichiasis phenotype through lymphscin- specification depends to some extent on tigraphy demonstrates lymph reflux in the proper Foxc1 activity. large lymphatic vessels of the leg, suggesting Although deficiency of forkhead agenesis or absence of valves in the collecting transcription factor Foxc2 results in defects lymphatic vessels (7). In addition, in contrast in lymphatic remodeling and failure to form to the lymphatic vessel hypoplasia or aplasia lymphatic valves (19), the precise function of seen in other forms of primary lymphedema, Foxc2 in this process has yet to be defined. FOXC2 haploinsufficient humans and mice Recently, it has been reported that integrin-α9 exhibit a hyperplastic lymphatic system mutant mice have a similar phenotype to (7,18,20,22,30). Indeed, failure of downregu- Foxc2-null mice, displaying abnormal lation of VEGFR3 and active VEGFR3 lymphatic valves and retrograde lymph flow signaling have been observed in FOXC2- and impaired fluid transport. Integrin-α9 has deficient lymphatic vessels (18).This finding been shown to be implicated in controlling indicates that reduced FOXC2 expression the formation of lymphatic valve leaflets (37). disrupts the normal balance between Further analysis shows that upregulation of lymphatic vessel growth promoting and Foxc2 transcription factor initiated the inhibiting genes. Interestingly, histological formation of the lymphatic valve followed by study revealed that the major proportion of the development of the valve leaflet, which skin lymphatic vessels was abnormally was initiated by upregulation of integrin-α9 invested by smooth muscle cells in patients expression during embryogenesis (18,37). On with FOXC2 mutations (19), which is in the other hand, Foxc2 like integrin-α9 is agreement with the findings in Foxc2-/- mice present in mature and developing lymphatic and indicates that FOXC2 is essential for the valves (37). In this light, it is tempting to morphogenesis of lymphatic valves and the speculate that Foxc2 acts upstream of establishment of a pericyte-free initial integrin-α9 in the formation of lymphatic lymphatic network (19). valves. But
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