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Royce Mohan, Akihiro Ishii, Ling Lei, Daniel Sheehy, Rashmi Bansal, Paola Bargagna-Mohan; A Novel Mouse Model of Corneal Neurofibroma in NF-1. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4068.
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Neurofibromatosis-1 (NF-1) is an autosomal dominant disorder that presents at birth through early childhood. The development of benign tumors (neurofibromas) in the ocular anterior segment (OAS) can compromise the function of the anterior chamber and lead to glaucoma. Corneal scarring and vascularization also feature in many patients with NF-1, which result from Schwann cell proliferation in the central corneal stroma. NF-1 is believed to result from over-activation of ERK driven by the MAPK-MEK pathway. Currently, there is very little known on the OAS aspects of NF-1 and hence we have developed a mouse model to investigate ocular disease resulting from MEK activation.
We developed a transgenic mouse line that constitutively expresses MEK controlled under the 2’, 3’-cyclic nucleotide 3’-phosphodiesterase (CNP) promoter. Heterozygous (Mek/+) and homozygous (Mek/Mek) transgenic mice were analyzed for developmental abnormalities at different postnatal stages (1.4 months to 8 months). Immunohistochemistry and western blot analysis was performed for fibrotic markers (vimentin, desmin, alpha-SMA, ERK) as well as Schwann cells markers (Oct6+ and Krox20+) and mast cell infiltration. Transmission electron microscopy was performed to analyze corneal nerves.
Mek/+ mice manifested a temporal pattern of increasing disease severity beginning around 3 months of age. Ocular proptosis, development of corneal neurofibromas, corneal scarring and vascularization became prominent by 6 months. Vimentin expression increased in Mek/+ corneas (1.4 months) preceding any noticeable clinical features of OAS pathology. By 6.3 months, vimentin became highly overexpressed, showed co-staining with phosphorylated ERK and the abundance of both immature (Oct6+) and myelinating (Krox20+) Schwann cells were observed in corneal stroma and iris. We also found age dependent closure of Schlemm’s canal by 6 months, which was preceeded by increased staining of pERK.There was also a massive invasion of mast cells and large blood vessels and presence of ectopic myelinated axons in the central cornea. The homozygous Mek/Mek mice presented with corneal disease earlier and clinically deteriorated more rapidly (4 months) indicative of gene dosage effects.
The Mek overexpressor mice serve as a useful model to study OAS disease manifestations of NF-1, which results from ERK hyperstimulation. This mouse model could also be exploited for therapeutic discovery.
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