September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Spatial and temporal dissection of pathogenesis in a mouse model of anterior segment dysgenesis and glaucoma caused by a Col4a1 mutation
Author Affiliations & Notes
  • Mao Mao
    Ophthalmology, Univ of California, SF Sch of Med, San Francisco, California, United States
  • Yvonne Ou
    Ophthalmology, Univ of California, SF Sch of Med, San Francisco, California, United States
  • Marton Kiss
    Ophthalmology, Univ of California, SF Sch of Med, San Francisco, California, United States
  • Douglas B Gould
    Ophthalmology, Univ of California, SF Sch of Med, San Francisco, California, United States
  • Footnotes
    Commercial Relationships   Mao Mao, None; Yvonne Ou, None; Marton Kiss, None; Douglas Gould, None
  • Footnotes
    Support  NIH Grant EY019887 EY002162
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 5146. doi:
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      Mao Mao, Yvonne Ou, Marton Kiss, Douglas B Gould; Spatial and temporal dissection of pathogenesis in a mouse model of anterior segment dysgenesis and glaucoma caused by a Col4a1 mutation. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5146.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Mutations in collagen type IV alpha 1 (COL4A1) cause anterior segment dysgenesis (ASD) that can lead to glaucoma. Because of the widespread distribution of COL4A1 in ocular basement membranes and the complex crosstalk between tissues of different embryological origin during development, dissecting the primary insults of pathogenesis can be difficult. Here, we use conditional expression of mutant COL4A1 to determine the primary location and timing of insults in ASD and glaucoma.

Methods : We developed a conditional allele with LoxP sites flanking exon 41 of Col4a1 (Col4a1flex41) that recreates the Col4a1Δex41 allele known to cause severe ASD in mice. We used Actb-Cre mice (ubiquitous CRE expression) to validate the Col4a1 flex41 allele for CRE-mediated excision. Next, we crossed Col4a1+/flex41 mice to three different tissue-specific CRE recombinase strains: MLR10-Cre (lens), Wnt1-Cre (neural crest derived periocular mesenchyme), and Tie2-Cre (vascular endothelial cells), to generate corresponding tissue-specific mutants. Finally, we used Rose26-CreERT mice (tamoxifen inducible CRE) to study the timing of pathogenesis. We tested the extent of ASD by performing slit-lamp examination, measuring intraocular pressure (IOP), and analyzing histological sections of anterior segment structures and optic nerves.

Results : Ubiquitous expression of mutant COL4A1 recapitulated the complete spectrum of ASD observed in Col4a1+/Δex41 mice, validating the conditional mutation. Using induction with tamoxifen we found that expressing the mutation after E12.5 did not cause ASD. Lens-specific mutants developed cataracts, mild ASD, IOP elevation, and optic nerve degeneration; however, other cell-type-specific mutants did not.

Conclusions : Our results suggest that early developmental events underlie ASD and that the lens is a primary site of pathogenesis. While lens-specific conditional mutants had cell-autonomous pathology, other mutant lines appeared to be normal. However, absence of ASD in those lines might due to compensation from other cell types and therefore their roles in the full manifestation of the phenotype cannot be ruled out – especially since lens-specific mutants did not fully phenocopy Col4a1+/Δex41 mice.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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