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Mao Mao, Douglas Gould; Dissecting the primary site of pathogenesis in COL4A1 related anterior segment dysgenesis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3057.
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© ARVO (1962-2015); The Authors (2016-present)
Anterior segment dysgenesis (ASD) is a spectrum of disorders affecting the development of anterior structures of the eye, leading to vision loss including glaucoma. Mutations in a basement membrane component, collagen type IV alpha1 (COL4A1) have been recently identified to cause ASD in mice and humans. As COL4A1 is present in all ocular basement membranes, and multiple tissues are affected in ASD, dissecting the primary site of pathogenesis can be difficult. Here, we assessed the primary location of insult in COL4A1 mediated ASD by utilizing conditional expression of mutant COL4A1.
Previously we characterized a Col4a1 mutant with a splice site mutation resulting in skipping of exon 41 (Col4a1 Δex41). To recreate the Col4a1 Δex41 allele, we developed a conditional allele with LoxP sites flanking exon 41 of Col4a1 (Col4a1 flox41). Three tissue-specific CRE recombinase lines were crossed with the Col4a1 +/flox41 mice to generate corresponding tissue-specific mutants. MLR10-Cre mice express CRE in whole lens at E10.5. Wnt1-Cre mice express CRE as early as E8.5 in neural crest derived tissues including periocular mesenchyme that give rise to multiple cell lineages of the anterior segment. In addition, as Col4a1 +/Δex41 mice have abnormal iris vasculature and anterior hyphema, Tie2-Cre mice expressing CRE in vascular endothelial cells were also included. Slit-lamp examination was performed to assess the extent of ASD. As Col4a1 +/Δex41 mice also develop optic nerve hypoplasia, histological analysis of the optic nerves was performed to assess if Col4a1 mutations also affect optic nerve development.
All three tissue-specific mutants developed ASD; however, the disease severity differed. While Col4a1 +/flox41; MLR10-Cre and Col4a1 +/flox41; Wnt1-Cre mice both had mild ASD that was characterized by abnormal iris vasculature and cataract, ASD in Col4a1 +/flox41; Tie2-Cre mice are more severe. In addition to abnormal iris vasculature and cataract, Col4a1 +/flox41; Tie2-Cre mice often had anterior synechia and enlarged anterior chamber. Moreover, Col4a1 +/flox41; Tie2-Cre had mild optic nerve hypoplasia while the other two mutants did not.
Our results suggest that ASD in Col4a1 mutant mice largely results from a primary insult from ocular vasculature. The mechanism of how abnormal ocular vasculature mutants lead to abnormal anterior segment development remains to be determined.
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