The homeodomain transcription factor PITX2 is required for specifying correct cell fates and establishing angiogenic privilege in the developing cornea

Dev Dyn. 2014 Nov;243(11):1391-400. doi: 10.1002/dvdy.24165. Epub 2014 Aug 1.

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.

Keywords: Dkk2; canonical Wnt signaling; glaucoma; ocular anterior segment; temporal gene knockout.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Differentiation / genetics
  • Cell Differentiation / physiology*
  • Cornea / blood supply
  • Cornea / embryology*
  • Cornea / metabolism
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology*
  • Gene Knockout Techniques
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mesenchymal Stem Cells / metabolism
  • Neovascularization, Physiologic / physiology*
  • Tamoxifen
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • DKK2 protein, human
  • Homeodomain Proteins
  • Intercellular Signaling Peptides and Proteins
  • Transcription Factors
  • Tamoxifen
  • homeobox protein PITX2