May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Dkk2 Is Downstream of Pitx2 and Required for Normal Eye Development
Author Affiliations & Notes
  • P. J. Gage
    Ophthalmology & Visual Science, Univ Michigan-Kellogg Eye Ctr, Ann Arbor, Michigan
  • K. I. Rosenberg
    Ophthalmology & Visual Science, Univ Michigan-Kellogg Eye Ctr, Ann Arbor, Michigan
  • M. Qian
    Ophthalmology & Visual Science, Univ Michigan-Kellogg Eye Ctr, Ann Arbor, Michigan
  • Footnotes
    Commercial Relationships P.J. Gage, None; K.I. Rosenberg, None; M. Qian, None.
  • Footnotes
    Support NIH Grants EY014125 & EY007003
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 3213. doi:
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      P. J. Gage, K. I. Rosenberg, M. Qian; Dkk2 Is Downstream of Pitx2 and Required for Normal Eye Development. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3213.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose:: Dkk2 encodes an extracellular antagonist of canonical Wnt signaling and was first implicated as downstream of the PITX2 homeodomain transcription factor in an unbiased screen of gene expression changes between wild type and mutant mice. The purpose of the current work was to test the hypothesis that Dkk2 is an essential PITX2-dependent regulator of mammalian eye development.

Methods:: Timed pregnant and post-natal litters were generated from Pitx2null and Dkk2null mice. Standard techniques of immunohistochemistry, RNA in situ hybridization, and light microscopy were used to compare gene expression and eye histology in wild type and mutant eyes.

Results:: Dkk2 is activated in ocular neural crest following expression of Pitx2. Dkk2 expression is lost in global and neural crest-specific Pitx2null/null mice, and mRNA levels are significantly reduced in Pitx2+/null mice. Dkk2null/null mice exhibit eyelid closure defects, anterior corneal stroma vascularization, and iridocorneal adhesions prior to birth. Postnatal defects include hypoplastic eyelids, ectopic eyelashes in the conjunctiva and limbus, corneal conjunctivalization, iris blood vessels extending to the central posterior cornea (Peter’s anomaly), and a progressive choroidal/scleral sheath surrounding the optic nerve. Molecular marker analysis showed that gene expression changes in both mesenchyme and the ocular surface ectoderm likely contribute to the underlying disease mechanisms and suggests an early bias of corneal ectoderm towards a conjunctival fate. Dorsal structures are frequently more affected, even though Dkk2 expression is symmetric.

Conclusions:: Dkk2 as an essential regulatory gene downstream of Pitx2 during eye development. Dkk2 is particularly important for normal anterior segment development, including eyelid growth, patterning the conjunctiva and cornea, and potentially establishment of the limbal barrier. Ectopic blood vessel growth in the corneal stroma, iris, and an abnormal sheath surrounding the optic nerve implies that DKK2 may also be required for blood vessel homeostasis. Changes in Dkk2/DKK2 expression likely underlie certain Pitx2 mutant phenotypes in mice and humans, and mutations to DKK2 may contribute to human eye disease.

Keywords: development • genetics • gene/expression 
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