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James Liu, Aman George, Brian Patrick Brooks; Zebrafish rere mutants exhibit optic nerve defects. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3326.
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© ARVO (1962-2015); The Authors (2016-present)
Human patients with the RERE gene mutation have been reported to display autism, coloboma, optic nerve and cerebral visual defects. In mouse models, Rere acts as a transcriptional co-repressor to regulate Shh signaling and Fgf8 expression from anterior signaling centers during embryonic development. Rere mRNA is expressed in developing mouse and zebrafish eyes and its loss of function is associated with microphthalmia.
To investigate the role of rere in optic nerve formation, we used zebrafish rere mutants (babtb210). Heterozygous rere mutant zebrafish were crossed with zebrafish expressing ath5:GFP, and then inbreed to generate homozygous rere mutants expressing ath5:GFP. Retinotectal projections were studied by injecting lipophilic fluorescent dyes in neural retina followed by confocal microscopy. Whole mount in situ hybridization was performed to study the changes in gene expression pattern.
Homozygous rere mutant embryos expressing ath5:GFP exhibit delayed optic nerve formation and axonal path finding errors by pioneer retinal ganglion cells as studies by time lapse confocal microscopy. At 48 hours post fertilization (hpf) we could observe patterning defects in retinal ganglion cell layer and thickened hypoplastic optic nerves in homozygous rere mutants as compared to wild type. Some of the optic nerve fibers failed to cross the midline at optic chiasm and projected to the ipsilateral optic tectum. Defects were mainly observed in the optic nerve fibers originating from the ventro-temporal neural retina as compared to the dorso-nasal side. The amount of optic nerve fibers reaching the optic tectum was also found to be significantly reduced, as measured by calculating the fluorescently labelled surface area of the optic tectum. At the molecular level we observed a significant reduction in the expression of retinal ganglion cell markers isl1 and cxcr4b at 32 and 48 hrs post fertilization. Expression of chemokine semaphorin3d and slit2 was significantly reduced in the preoptic area of rere mutant embryos as compared to wild type, whereas pax2, fgf8, cxcl12a and netrin1 expression was expanded in the optic stalk.
Our study suggests that zebrafish rere plays an important role in establishment of visual function pathway by regulating proper pattering of the optic stalk.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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