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Pieter Norden, Lisa Beckmann, Xian Zhang, Hao F Zhang, Tsutomu Kume; Foxc2 is required in the neural crest for proper development of Schlemm's Canal. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4309. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The Schlemm’s Canal (SC), located in the iridocorneal angle, is a vessel characterized by both venous and lymphatic identity that has a key role in intraocular pressure maintenance in physiological and pathological conditions in regulating aqueous humor outflow along with the trabecular meshwork. The Angpt/TEK and VEGFC/VEGFR3 signaling pathways have been demonstrated to regulate SC development and maintenance, but mechanisms of paracrine signaling from the neighboring tissues and cells contributing to SC development are poorly understood. Our laboratory demonstrated that neural crest (NC)-derived periocular mesenchymal cells require expression of the Forkhead box (Fox) transcription factor Foxc2 for proper development of the anterior segment (Seo et al. IOVS 2017); however, it’s role in contribution to the development of the SC has yet to be investigated.
Foxc2 was deleted from NC-derived cells by crossing Foxc2F mice with Wnt1-Cre mice. Eyes of NC-Foxc2-/- mutants and Cre- negative mice were imaged in vivo using a custom built visible light optical coherence tomography (vis-OCT) system which captured the entire 360 degrees of the SC and its surrounding vessels in 8 separate raster scans which were then post-processed. Resolution of the system in tissue was about 5 μm laterally and 1 μm axially. OCT angiography was performed by taking 5 repeated B scans at each location, using motion contrast to visualize the blood vessels surrounding the SC. Immunohistochemistry for characterization of SC morphology was performed on flatmounted eyes where the lens and retina tissues had been removed.
vis-OCT image volumes showed different levels of narrowed and discontinuous SC morphology in the NC-Foxc2-/- mutants while OCT angiography showed various levels of corneal neovascularization . Immunostaining of PECAM1 and Prox1 identified abnormal SC morphology, or the absence of SC, in NC-Foxc2-/- mutants compared to Cre-negative mice in addition to corneal neovascularization from the blood and lymphatic limbus vasculature.
In addition to previously demonstrated phenotypes associated with corneal conjuctivalization, neovascularization, and disrupted ocular epithelial cell identity, the NC-Foxc2 mutation is also associated with maldevelopment of the SC. These results demonstrate that Foxc2 expression in the NC lineage is required for paracrine signaling to the SC vasculature for proper development.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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