Abstract

Mutations in genes that code for components of the Norrin-FZD4 ligand-receptor complex cause the inherited childhood blinding disorder familial exudative vitreoretinopathy (FEVR). Statistical evidence from studies of patients at risk for the acquired disease retinopathy of prematurity (ROP) suggest that rare polymorphisms in these same genes increase the risk of developing severe ROP, implying that decreased Norrin-FZD4 activity predisposes patients to more severe ROP. To test this hypothesis, we measured the development and recovery of retinopathy in wild type and Fzd4 heterozygous mice in the absence or presence of ocular ischemic retinopathy (OIR) treatment. Avascular and total retinal vascular areas and patterning were determined, and vessel number and caliber were quantified. In room air, there was a small delay in retinal vascularization in Fzd4 heterozygous mice that resolved as mice reached maturity suggestive of a slight defect in retinal vascular development. Subsequent to OIR treatment there was no difference between wild type and Fzd4 heterozygous mice in the vaso-obliterated area following exposure to high oxygen. Importantly, after return of Fzd4 heterozygous mice to room air subsequent to OIR treatment, there was a substantial delay in retinal revascularization of the avascular area surrounding the optic nerve, as well as delayed vascularization toward the periphery of the retina. Our study demonstrates that a small decrease in Norrin-Fzd4 dependent retinal vascular development lengthens the period during which complications from OIR could occur.

Highlights

  • The retina is a thin layer of neural tissue lining the back of the eye responsible for sensing visual stimuli

  • We determined the status of retinal vascular development in Fzd4+/- mice raised in room air to determine if Fzd4 haploinsufficiency had an effect on vascular development

  • Retinal vessel caliber measured as a percentage of vessels >50 μm was increased in the proximal and mid regions in Fzd4+/- mice compared to wild type mice at postnatal day 12 (P12), while vessel caliber was decreased in the distal region (Fig 2)

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Summary

Introduction

The retina is a thin layer of neural tissue lining the back of the eye responsible for sensing visual stimuli. Rare polymorphisms in three of the known FEVR genes, NDP, FZD4 and LRP5 have been identified in patients with severe ROP in various populations [4, 30,31,32,33,34,35,36,37,38] suggesting that small defects in Norrin-FZD4 signaling may affect the development of ROP. We determined that Fzd4+/- mice subjected to OIR displayed a substantive defect in revascularization following re-exposure to room air compared to wild type mice This is the first functional demonstration that a small decrease in Norrin-Fzd dependent retinal vascular development lengthens the period of vascular recovery subsequent to OIR. Polymorphisms in the genes encoding components of the Norrin-FZD4 pathway in infants that developed more severe ROP

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