September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
IRE1 Signaling Associated With Retinal Vascular Lesions Caused By Mutant COL4A1
Author Affiliations & Notes
  • Marcel Victor Alavi
    Department of Ophthalmology, University of California, San Francisco, San Francisco, California, United States
  • Douglas B Gould
    Department of Ophthalmology, University of California, San Francisco, San Francisco, California, United States
  • Footnotes
    Commercial Relationships   Marcel Alavi, None; Douglas Gould, None
  • Footnotes
    Support  NIH Grants: EY019514 and EY02162
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2727. doi:
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      Marcel Victor Alavi, Douglas B Gould; IRE1 Signaling Associated With Retinal Vascular Lesions Caused By Mutant COL4A1. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2727.

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

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Abstract

Purpose : Type IV collagens are major components of basement membranes. Dominant negative mutations in the genes encoding COL4A1 and COL4A2 cause multisystem disorders including porencephaly, brain small vessel disease with or without ocular anomalies, and hereditary angiopathy with nephropathy, aneurysms, and muscle cramps. In the retina, COL4A1 and COL4A2 mutations lead to arterial tortuosity and cause progressive vascular lesions. Mutant collagen elicited ER stress and activation of the unfolded protein response under some conditions and was undetectable in other experimental paradigms. Here we investigated the role of the unfolded protein response in the development and progression of retinal vascular lesions in Col4a1 mutant mice.

Methods : Transgenic ER stress activated indicator (ERAI) reporter mice express GFP upon XBP1 mRNA splicing by IRE1 during ER stress. We crossed Col4a1+/Δex41 with ERAI mice to generate Col4a1+/Δex41;ERAI mice, which enabled us to monitor unfolded protein response activation in the retina in vivo by fluorescence ophthalmoscopy and in situ by immunohistochemistry. All studies and procedures were performed in accordance with the guidelines of the UCSF IACUC and in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Results : We quantified levels of several unfolded protein response markers by qPCR and found a small but significant increase of Xbp1 splicing in retinal samples from Col4a1+/Δex41 mice compared to Col4a1+/+ mice. Retinal lesions in Col4a1+/Δex41;ERAI mice were associated with increased GFP fluorescence signals indicative of IRE1 activation. Cells surrounding the retinal lesions showed strong antibody staining against GFP while intact parts of Col4a1+/Δex41;ERAI retinas showed similar staining patterns to Col4a1+/+;ERAI mice.

Conclusions : The IRE1 pathway was significantly activated at sites of lesions in Col4a1+/Δex41 retinas. Against our expectations, vascular endothelial cells, the source of COL4A1 in the mouse retina, did not show increased IRE1 activation. Our findings suggest that IRE1 activation is a consequence rather than the cause of retinal lesions in Col4a1+/Δex41;ERAI retinas.

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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