Discs of mammalian rod photoreceptors form through the membrane evagination mechanism

Ding, Jindong; Salinas, Raquel Y.; Arshavsky, Vadim Y.

doi:10.1083/jcb.201508093

Cited by 107 publications

(129 citation statements)

References 33 publications

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“…This remarkable rate of membrane turnover and RPE phagocytosis is balanced by daily disc regeneration, but an understanding of the cellular process of regeneration of new photoreceptor discs has been poorly understood. Recently, new electron microscopy methodologies have revealed that OS discs are formed through a process of membrane evagination and indicate a highly regulated and ordered process at play in building photoreceptor discs (11)(12)(13). Rhodopsin is not only a photoreceptor but is a required structural component for disc membrane formation.…”

Section: Docosahexaenoic Acid (Dha)mentioning

confidence: 99%

“…The early postnatal reduction in OS length without photoreceptor cell death was a striking feature of Mfsd2a KO retinas. The OS contains photoreceptor disc membranes that form through membrane biogenesis in the IS (11)(12)(13), occurring on a daily basis to balance photoreceptor disc turnover at the distal OS via phagocytosis by the RPE (10). It can be imagined that this high level of membrane biogenesis to build OS discs would apply unique metabolic demands on the retina.…”

Section: Srebp1cmentioning

confidence: 99%

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Mfsd2a Is a Transporter for the Essential ω-3 Fatty Acid Docosahexaenoic Acid (DHA) in Eye and Is Important for Photoreceptor Cell Development

Wong

Chan

Cazenave-Gassiot

et al. 2016

Journal of Biological Chemistry

120

140

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Eye photoreceptor membrane discs in outer rod segments are highly enriched in the visual pigment rhodopsin and the -3 fatty acid docosahexaenoic acid (DHA). The eye acquires DHA from blood, but transporters for DHA uptake across the bloodretinal barrier or retinal pigment epithelium have not been identified. Mfsd2a is a newly described sodium-dependent lysophosphatidylcholine (LPC) symporter expressed at the bloodbrain 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. Docosahexaenoic acid (DHA)2 is a conditionally essential -3 fatty acid highly enriched in neuronal tissues such as the brain and eye and is considered to be required for normal development and function of these tissues (1, 2), but the function of DHA in the retina is not understood. Within the eye, DHA is primarily found in phospholipids of photoreceptor outer segment (OS) membrane discs localized together with the photoreceptor rhodopsin (3) accounting for the highest body concentration of DHA per unit area (1). Like in brain, the eye does not synthesize DHA de novo, but must import it from the blood (1).The eye contains two cellular barriers that prevent the diffusion of blood-borne material from entering the retina, the blood-retinal barrier (BRB) formed by the endothelium of retinal capillaries and the retinal pigment epithelium (RPE) at the back of the eye (4). DHA must cross these barriers for ultimate delivery to photoreceptor discs, but the contribution of either of these routes, via the BRB or RPE, to DHA uptake in the eye is unclear. Photoreceptors in OS discs exposed to daylight accumulate photo-damaged proteins and lipids over time (5). To cope with photo-damaged discs, photoreceptor outer segment discs undergo a constant renewal process for the maintenance of its excitability ...

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Section: Docosahexaenoic Acid (Dha)mentioning

confidence: 99%

Section: Srebp1cmentioning

confidence: 99%

Mfsd2a Is a Transporter for the Essential ω-3 Fatty Acid Docosahexaenoic Acid (DHA) in Eye and Is Important for Photoreceptor Cell Development

Wong

Chan

Cazenave-Gassiot

et al. 2016

Journal of Biological Chemistry

120

140

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“…The alternative hypothesis (ii) rests on the fact that a number of basal discs (and possibly distal discs) of the rod OS are not closed and internalized in the OS, but rather like classic cone discs are contiguous with the plasma membrane (61,62) (Fig. 5).…”

Section: Estimating the Spring Constant Of An Elementary Rod Os Elasticmentioning

confidence: 99%

In vivo optophysiology reveals that G-protein activation triggers osmotic swelling and increased light scattering of rod photoreceptors

Zhang

Zawadzki

Goswami

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

164

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The light responses of rod and cone photoreceptors have been studied electrophysiologically for decades, largely with ex vivo approaches that disrupt the photoreceptors' subretinal microenvironment. Here we report the use of optical coherence tomography (OCT) to measure light-driven signals of rod photoreceptors in vivo. Visible light stimulation over a 200-fold intensity range caused correlated rod outer segment (OS) elongation and increased light scattering in wildtype mice, but not in mice lacking the rod G-protein alpha subunit, transducin (Gα t ), revealing these responses to be triggered by phototransduction. For stimuli that photoactivated one rhodopsin per Gα t the rod OS swelling response reached a saturated elongation of 10.0 ± 2.1%, at a maximum rate of 0.11% s −1. Analyzing swelling as osmotically driven water influx, we find the H 2 O membrane permeability of the rod OS to be (2.6 ± 0.4) × 10 −5 cm·s, comparable to that of other cells lacking aquaporin expression. Application of Van't Hoff's law reveals that complete activation of phototransduction generates a potentially harmful 20% increase in OS osmotic pressure. The increased backscattering from the base of the OS is explained by a model combining cytoplasmic swelling, translocation of dissociated G-protein subunits from the disc membranes into the cytoplasm, and a relatively higher H 2 O permeability of nascent discs in the basal rod OS. Translocation of phototransduction components out of the OS may protect rods from osmotic stress, which could be especially harmful in disease conditions that affect rod OS structural integrity.osmotic stress | phototransduction | optical coherence tomography | intrinsic optical signals | photoreceptor waveguiding

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“…This realization, combined with evidence of vesicles in the connecting cilium seen in electron micrographs, has been taken to support the model that vesicles are actively transported through the connecting cilium and generate nascent discs by membrane fusion at the base of the outer segment (Chuang et al, 2007(Chuang et al, , 2015. Ding et al (2015) addressed these competing hypotheses with two distinct approaches. First, they treated sections of retinas of mice perfused with a membrane-staining mixture of tannic acid and uranyl acetate and performed EM.…”

mentioning

confidence: 98%

Photoreceptor disc morphogenesis: The classical evagination model prevails

Pugh¹

2015

J Gen Physiol

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Discs of mammalian rod photoreceptors form through the membrane evagination mechanism

Cited by 107 publications

References 33 publications

Mfsd2a Is a Transporter for the Essential ω-3 Fatty Acid Docosahexaenoic Acid (DHA) in Eye and Is Important for Photoreceptor Cell Development

Mfsd2a Is a Transporter for the Essential ω-3 Fatty Acid Docosahexaenoic Acid (DHA) in Eye and Is Important for Photoreceptor Cell Development

In vivo optophysiology reveals that G-protein activation triggers osmotic swelling and increased light scattering of rod photoreceptors

Photoreceptor disc morphogenesis: The classical evagination model prevails

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