title: The homeodomain transcription factor PITX2 is required for specifying correct cell fates and establishing angiogenic privilege in the developing cornea.
abstract: BACKGROUND
  Correct specification of cell lineages and establishing angiogenic privilege within the developing cornea are essential for normal vision but the mechanisms controlling these processes are poorly understood.
  
  
  RESULTS
  We show that the homeodomain transcription factor PItX2 is expressed in mesenchymal cells of the developing and mature cornea and use a temporal gene knockout approach to demonstrate that PITX2 is required for corneal morphogenesis and the specification of cell fates within the surface ectoderm and mesenchymal primordia. PITX2 is also required to establish angiogenic privilege in the developing cornea. Further, the expression of Dkk2 and suppression of canonical Wnt signaling activity levels are key mechanisms by which PITX2 specifies ocular surface ectoderm as cornea. In contrast, specifying the underlying mesenchyme to corneal fates and establishing angiogenic privilege in the cornea are less sensitive to DKK2 activity. Finally, the cellular expression patterns of FOXC2, PITX1, and BARX2 in Pitx2 and Dkk2 mutants suggest that these transcription factors may be involved in specifying cell fate and establishing angiogenic privilege within the corneal mesenchyme. However, they are unlikely to play a role in specifying cell fate within the corneal ectoderm.
  
  
  CONCLUSIONS
  Together, these data provide important insights into the mechanisms regulating cornea development.
authors.affiliation: Department of Ophthalmology and Visual Science, University of Michigan Medical School, Ann Arbor, Michigan; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Gage
authors.forename: Chen
authors.initials: C
authors.lastname: Kuang
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Zacharias
mesh_terms: D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D003315:Cornea / Q000098:blood supply / Q000196:embryology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D055786:Gene Knockout Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D013629:Tamoxifen; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D013629:Tamoxifen; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C498622:DKK2 protein, human
keywords: Dkk2; canonical Wnt signaling; glaucoma; ocular anterior segment; temporal gene knockout