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Bernadett Bosze, Brian S. Clark, Seth Blackshaw, Nadean L Brown; Optic nerve head development in the embryonic mouse eye. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3839.
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The optic nerve head (ONH) is a cuff of cells encircling the optic nerve and constitutes a boundary between presumptive neural retina and glial-derived optic stalk. The ONH represents a pathogenic hub for glaucoma and has also been associated with pediatric disorders including the incomplete closure of the embryonic fissure (coloboma). A number of genetic mutations have been linked to ONH abnormalities, including Pax2, which plays an important role in establishing and maintaining the ONH identity. We further identified Hes1, a downstream effector of the Notch signaling pathway with a central role in ONH genesis. Using Hes1 and Pax2 mutant mouse models, we examined the transcriptional landscape of the embryonic ONH.
We have generated early, retina-specific deletions of Hes1 and used immunohistochemistry to assess embryonic ONH development. We also took advantage of restricted GFP expression in Pax2GFP knock-in mice and used flow cytometry to isolate GFP+ ONH cells from control, Hes1 mutant and Pax2 mutant retinas at three developmental time point and performed bulk RNA-Seq.
Hes1 expression is sustained at the ONH. Hes1 mutant retinas are microphthalmic (small eyes), Pax2 expression is both mispatterned and mispositioned, yet its activation and maintenance are unaffected. Additionally, in both Hes1 and Pax2 mutants, Pax6/Pax2 boundary shifts proximally leading to an elongated shape of the retina. Retinal ganglion cell (RGC) axons are misrouted and project toward the lens.
Our results show that sustained Hes1 expression at the ONH helps organize boundaries within the forming optic cup and consequently regulates RGC axon assembly and exit through the ONH. We also predict a possible interaction between Hes1 and Pax2 that modulates ONH identity. Furthermore, differentially expressed transcripts will help uncover gene pathways involved in ONH formation. This work advances our understanding of optic nerve head development and has important implications for potential treatment of congenital eye diseases.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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