title: Foxc1 and Foxc2 in the Neural Crest Are Required for Ocular Anterior Segment Development.
abstract: The large Forkhead (Fox) transcription factor family has essential roles in development, and mutations cause a wide range of ocular and nonocular disease. One member, Foxc2 is expressed in neural crest (NC)-derived periocular mesenchymal cells of the developing murine eye; however, its precise role in the development, establishment, and maintenance of the ocular surface has yet to be investigated.
  
  
  
  To specifically delete Foxc2 from NC-derived cells, conditional knockout mice for Foxc2 (NC-Foxc2-/-) were generated by crossing Foxc2F mice with Wnt1-Cre mice. Similarly, we also generated compound NC-specific mutations of Foxc2 and a closely related gene, Foxc1 (NC-Foxc1-/-;NC-Foxc2-/-) in mice.
  
  
  
  Neural crest-Foxc2-/- mice show abnormal thickness in the peripheral-to-central corneal stroma and limbus and displaced pupils with irregular iris. The neural crest-specific mutation in Foxc2 also leads to ectopic neovascularization in the cornea, as well as impaired ocular epithelial cell identity and corneal conjunctivalization. Compound, NC-specific Foxc1; Foxc2 homozygous mutant mice have more severe defects in structures of the ocular surface, such as the cornea and eyelids, accompanied by significant declines in the expression of another key developmental factor, Pitx2, and its downstream effector Dkk2, which antagonizes canonical Wnt signaling.
  
  
  
  The neural crest-Foxc2 mutation is associated with corneal conjunctivalization, ectopic corneal neovascularization, and disrupted ocular epithelial cell identity. Furthermore, Foxc2 and Foxc1 cooperatively function in NC-derived mesenchymal cells to ensure proper morphogenesis of the ocular surface via the regulation of Wnt signaling. Together, Foxc2 is required in the NC lineage for mesenchymal-epithelial interactions in corneal and ocular surface development.
authors.affiliation: Feinberg Cardiovascular Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States 2Department of Life Science, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, Korea.
authors.forename: Seungwoon
authors.initials: S
authors.lastname: Seo
authors.affiliation: Department of Ophthalmology and Visual Science, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, United States.
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Liu
authors.affiliation: Feinberg Cardiovascular Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States.
authors.forename: Demin
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Feinberg Cardiovascular Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Schultz
authors.affiliation: Feinberg Cardiovascular Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Sasman
authors.affiliation: Feinberg Cardiovascular Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, United States.
authors.forename: Hao F
authors.initials: HF
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology and Visual Science, University of Michigan, Ann Arbor, Michigan, United States.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Gage
authors.affiliation: Feinberg Cardiovascular Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kume
mesh_terms: D000818:Animals; D000869:Anterior Eye Segment / Q000196:embryology* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D005451:Fluorescein Angiography; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D005654:Fundus Oculi; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009154:Mutation; D009432:Neural Crest / Q000196:embryology / Q000378:metabolism*; D038081:Organogenesis / Q000235:genetics*; D012160:Retina / Q000196:embryology / Q000378:metabolism; D015398:Signal Transduction; D041623:Tomography, Optical Coherence
chemical_list: D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse; C082078:mesenchyme fork head 1 protein; D004247:DNA