June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Pitx2 Regulates Early Neural Crest Migration in Periocular Mesenchyme
Author Affiliations & Notes
  • Bahaar Chawla
    Ophthalmology and Visual Science, University of Michigan Health System, Ann Arbor, MI
  • Antionette L Williams
    Ophthalmology and Visual Science, University of Michigan Health System, Ann Arbor, MI
  • Brenda L Bohnsack
    Ophthalmology and Visual Science, University of Michigan Health System, Ann Arbor, MI
  • Footnotes
    Commercial Relationships Bahaar Chawla, None; Antionette Williams, None; Brenda Bohnsack, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 5480. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Bahaar Chawla, Antionette L Williams, Brenda L Bohnsack; Pitx2 Regulates Early Neural Crest Migration in Periocular Mesenchyme. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5480.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose: Mutations in the PITX2 gene are associated with the congenital eye disease, Axenfeld-Rieger Syndrome (ARS). Pitx2, which is expressed in the neural crest-derived periocular mesenchyme, is regulated by the essential morphogen, retinoic acid (RA). In these studies, we used zebrafish to further elucidate the role of RA and pitx2 in neural crest and eye development.

Methods: Morpholino oligonucleotides (MO) and mRNA injections were used in combination with exogenous regulators of RA. Time-lapse imaging of transgenic zebrafish expressing GFP in neural crest assessed migration. Embryos were harvested for in situ hybridization, immunostaining, TUNEL assay, and histology.

Results: Time-lapse imaging demonstrated that the neural crest migrated in waves that were dorsal and ventral to the developing eye. Both MO knockdown and overexpression of Pitx2 completely suppressed the ventral wave of neural crest migration. Alterations in Pitx2 levels also disrupted the dorsal wave, causing the neural crest cells to improperly migrate and undergo apoptosis. These findings were mirrored in embryos where RA synthesis was genetically decreased (Raldh2 MO) or increased (raldh2 mRNA). Further, improper early neural crest migration into the craniofacial region and periocular mesenchyme inhibited later neural crest migration into the eye. RA induced pitx2 expression in the neural crest via RA receptor (RAR) A2A, A2B, and GA and together RA and Pitx2 regulated retinal and neural crest cell proliferation in the developing eye. Alterations in RA or Pitx2 levels prevented the cells from exiting the cell cycle leading to a higher proportion of retinal and neural crest cells in S-phase. Disruption in cellular migration and proliferation resulted in increased apoptosis throughout the developing eye.

Conclusions: RA regulation of Pitx2 in the neural crest-derived periocular mesenchyme was essential for early neural crest migration into the craniofacial region and later NC and retinal proliferation and survival.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×