Purpose
Foxc1 and Foxc2, members of the forkhead/Fox transcription factor family, are critical regulators of vascular development. Foxc1 and Foxc2 are both expressed in ocular mesenchymes of neural crest origin. However, little is known about the role of Foxc1 and Foxc2 in ocular development, mainly due to the mid-gestation lethality of global knockout mice. Previously, we have demonstrated that deletion of Foxc1 in neural crest-derived cells (NCC) leads to aberrant vessel growth in the normally avascular corneas of mice, and that the effect is cell-type specific, because the corneas of mice lacking Foxc1 expression in vascular endothelial cells remained avascular. Therefore, we investigate the role of Foxc1 and Foxc2 in NCC during ocular development.
Methods
To specifically delete Foxc1 and/or Foxc2 from NCC, conditional knockout mice for Foxc2 (NC-Foxc2-/-) and for Foxc1 and Foxc2 (NC-Foxc1-/-; Foxc2-/-) were generated by crossing floxed-Foxc1 and floxed-Foxc2 mice with Wnt1-cre mice.
Results
Adult NCC-specific Foxc2 mutant mice exhibit corneal neovascularization and lymphangiogenesis. Mutant eyes exhibit abnormal thickness in the peripheral-to-central corneal stroma and limbus (Figure 1). Interestingly, some mutant corneas have hyperplastic stroma with increased cell density. Mutant pupils are displaced from the normal central position. The anterior chamber is normally formed in NC-Foxc2-/- mice, but not in NC-Foxc1-/-; Foxc2-/- mice. The severity of the ocular phenotype is dependent on the cumulative “dose” of functional Foxc1 and Foxc2 genes and abnormalities are more extensive in NC-Foxc1-/-; Foxc2-/-. In fact, in NC-Foxc1-/-; Foxc2-/- mice the cornea is not present at all (Figure 1). In the alkali-burn model, corneas of adult NC-Foxc2+/- mice and NC-Foxc1+/-; Foxc2+/- mice have increased corneal neovascularization and lymphangiogenesis compared with those of control mice (Figure 2).
Conclusions
Taken together, these data suggest that the overlapping function of Foxc1 and Foxc2 in the neural crest plays an important role in maintaining corneal avascularity and development of the anterior eye segment.
Keywords: 609 neovascularization •
484 cornea: stroma and keratocytes •
497 development