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Loss of Zebrafish Mfrp Causes Nanophthalmia, Hyperopia, and Accumulation of Subretinal Macrophages. Invest Ophthalmol Vis Sci 2016 12 01;57(15):6805-6814



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2-s2.0-85007349845   16 Citations


Purpose: Mutations in membrane frizzled-related protein (MFRP) are associated with nanophthalmia, hyperopia, foveoschisis, irregular patches of RPE atrophy, and optic disc drusen in humans. Mouse mfrp mutants show retinal degeneration but no change in eye size or refractive state. The goal of this work was to generate zebrafish mutants to investigate the loss of Mfrp on eye size and refractive state, and to characterize other phenotypes observed.

Methods: Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 methods were used to generate multiple frameshift mutations in zebrafish mfrp causing premature translational stops in Mfrp. Spectral-domain optical coherence tomography (SD-OCT) was used to measure eye metrics and refractive state, and immunohistochemistry was used to study adult eyes. Gene expression levels were measured using quantitative PCR.

Results: Zebrafish Mfrp was shown to localize to apical and basal regions of RPE cells, as well as the ciliary marginal zone. Loss of Mfrp in mutant zebrafish was verified histologically. Zebrafish eyes that were mfrp mutant showed reduced axial length causing hyperopia, RPE folding, and macrophages were observed subretinally. Visual acuity was reduced in mfrp mutant animals.

Conclusions: Mutation of zebrafish mfrp results in hyperopia with subretinal macrophage infiltration, phenocopying aspects of human and mouse Mfrp deficiency. These mutant zebrafish will be useful in studying the onset and progression of Mfrp-related nanophthalmia, the cues that initiate the recruitment of macrophages, and the mechanisms of Mfrp function.

Author List

Collery RF, Volberding PJ, Bostrom JR, Link BA, Besharse JC


Ross F. Collery PhD Assistant Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
Brian A. Link PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

DNA Mutational Analysis
Intracellular Signaling Peptides and Proteins
Polymerase Chain Reaction
Retinal Degeneration
Retinal Pigment Epithelium
Tomography, Optical Coherence
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