September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Zebrafish atr2 gene is required for optic fissure closure
Author Affiliations & Notes
  • Aman George
    OGVFB, NEI/NIH, BETHESDA, Maryland, United States
  • Jerry Lee
    OGVFB, NEI/NIH, BETHESDA, Maryland, United States
  • sunit Dutta
    OGVFB, NEI/NIH, BETHESDA, Maryland, United States
  • Brian Patrick Brooks
    OGVFB, NEI/NIH, BETHESDA, Maryland, United States
  • Footnotes
    Commercial Relationships   Aman George, None; Jerry Lee, None; sunit Dutta, None; Brian Brooks, None
  • Footnotes
    Support  NEI intramural
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 6577. doi:
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      Aman George, Jerry Lee, sunit Dutta, Brian Patrick Brooks; Zebrafish atr2 gene is required for optic fissure closure. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6577.

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

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Abstract

Purpose : Atr2, also known as rere is a transcriptional co-repressor protein and is known to regulate Sonic hedgehog (Shh) and fibroblast growth factor (Fgf) 8 expression from anterior signaling centers during mouse embryo development. Atr2 mRNA is expressed in the developing mouse and zebrafish eyes and the zebrafish bab mutants and RERE om/eyes3 mutant mouse which survive post post-natally exhibit severe microphthalmia. The present study was thus carried out to study the role of atr2 in eye development and specifically its role in optic fissure closure (OFC) and the underlying mechanism

Methods : We used the zebrafish babtb210 mutants and morpholino mediated knockdown strategy to investigate the role of atr2 in regulating expression of genes required for eye development and optic fissure closure, using in situ hybridization technique.

Results : Here we report that morpholino mediated knockdown of atr2 in zebrafish embryos causes OFC defects and the zebrafish bab mutants exhibit delayed optic fissure closure. Atr2 depleted, 24 hours post fertilized embryos exhibit upregulation of fgf8a and pax2.1, and down-regulation of pax6, vax2 and nlz1 in the neural retina and ventral optic cup, respectively. The patterning of the eye along the dorso-ventral axis was not disrupted as studied by the expression of aldh1a3 and aldh1a2, respectively. Increased fgf8a and pax2.1 expression, and decreased expression of pax6, nlz1 and vax2 expression has been associated with presence of OFC defects previously.
Since fgf8 is the known signaling molecule involved in the patterning of the neural retina, we studied whether defects similar to bab mutants can be recapitulated just by overexpression of fgf8. We used the transgenic HSP70:fgf8a zebrafish line to overexpress fgf8 at 5-10, 15-20 somite and 20 somite-prim5 stages of zebrafish development. Over-expression of fgf8a at earlier stages (5-20s) caused OFC defects and 20s-prim5 it caused severe microphthalmia. Morpholino mediated co-knockdown of fgf8 along with atr2 rescued OFC defects in a dose dependent manner, whereas fgf8a knockdown alone did not cause any eye defects.

Conclusions : The zebrafish can be a good model system to study human conditions associated with ATR2 mutation such as cerebral visual impairments, as it is conserved structurally and functionally in zebrafish, mouse and humans.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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