Wong BH(1), Chan JP(1), Cazenave-Gassiot A(2), Poh RW(3), Foo JC(2), Galam DL(1), Ghosh S(4), Nguyen LN(5), Barathi VA(6), Yeo SW(7), Luu CD(8), Wenk MR(2), Silver DL(9)

(1)From the Signature Research Program in Cardiovascular and Metabolic Disorders.

(2)the Department of Biochemistry, National University of Singapore, 8 Medical Drive, Block MD 7, Singapore 117597, Singapore.

(3)the Carl Zeiss Pte. Ltd., Microscopy Business Group, Singapore, 50 Kaki Bukit Place, 05-01, Singapore 415926, Singapore.

(4)From the Signature Research Program in Cardiovascular and Metabolic Disorders, Centre for Computational Biology, and.

(5)the Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Building MD4, Level 1-03A, Singapore 117545, Singapore.

(6)the Singapore Eye Research Institute, 11 Third Hospital Ave., Singapore 168751, Singapore, the Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Rd 119228, NUHS Tower Block,Level 11, Singapore 117597, Singapore, and ACP Ophthalmology, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singapore.

(7)the Singapore Eye Research Institute, 11 Third Hospital Ave., Singapore 168751, Singapore.

(8)the Singapore Eye Research Institute, 11 Third Hospital Ave., Singapore 168751, Singapore, the Centre for Eye Research Australia, Level 1, 32 Gisborne St., East Melbourne, Victoria 3002, Australia.

(9)From the Signature Research Program in Cardiovascular and Metabolic

Abstract

Eye photoreceptor membrane discs in outer rod segments are highly enriched in the visual pigment rhodopsin and the ω-3 fatty acid docosahexaenoic acid (DHA). The eye acquires DHA from blood, but transporters for DHA uptake across the blood-retinal barrier or retinal pigment epithelium have not been identified. Mfsd2a is a newly described sodium-dependent lysophosphatidylcholine (LPC) symporter expressed at the blood-brain barrier that transports LPCs containing DHA and other long-chain fatty acids. LPC transport via Mfsd2a has been shown to be necessary for human brain growth. Here we demonstrate that Mfsd2a is highly expressed in retinal pigment epithelium in embryonic eye, before the development of photoreceptors, and is the primary site of Mfsd2a expression in the eye. Eyes from whole body Mfsd2a-deficient (KO) mice, but not endothelium-specific Mfsd2a-deficient mice, were DHA-deficient and had significantly reduced LPC/DHA transport in vivo Fluorescein angiography indicated normal blood-retinal barrier function. Histological and electron microscopic analysis indicated that Mfsd2a KO mice exhibited a specific reduction in outer rod segment length, disorganized outer rod segment discs, and mislocalization of and reduction in rhodopsin early in postnatal development without loss of photoreceptors. Minor photoreceptor cell loss occurred in adult Mfsd2a KO mice, but electroretinography indicated visual function was normal. The developing eyes of Mfsd2a KO mice had activated microglia and up-regulation of lipogenic and cholesterogenic genes, likely adaptations to loss of LPC transport. These findings identify LPC transport via Mfsd2a as an important pathway for DHA uptake in eye and for development of photoreceptor membrane discs.

Keywords

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