Retinoid X Receptor γ Is Necessary to Establish the S-opsin Gradient in Cone Photoreceptors of the Developing Mouse Retina

We describe the first extensive study of voltage-clamp current responses of cone photoreceptors in unlabeled, dark-adapted mouse retina using only the position and appearance of cone somata as a guide. Identification was confirmed from morphology after dye filling. Photocurrents recorded from wild-type mouse cones were biphasic with a fast cone component and a slower rod component. The rod component could be eliminated with dim background light and was not present in mouse lines lacking the rod transducin-α subunit (Gnat1−/−) or connexin 36 (Cx36−/−). Cones from Gnat1−/− or Cx36−/− mice had resting membrane potentials between −45 and −55 mV, peak photocurrents of 20–25 picoamps (pA) at a membrane potential Vm = −50 mV, sensitivities 60–70 times smaller than rods, and a total membrane capacitance two to four times greater than rods. The rate of activation (amplification constant) was largely independent of the brightness of the flash and was 1–2 s−2, less than half that of rods. The role of Ca2+-dependent transduction modulation was investigated by recording from cones in mice lacking rod transducin (Gnat1), recoverin, and/or the guanylyl-cyclase–activating proteins (GCAPs). In confirmation of previous results, responses of Gnat1−/−;Gcaps−/− cones and triple-mutant Gnat1−/−;Gcaps−/−;Rv−/− cones recovered more slowly both to light flashes and steps and were more sensitive than cones expressing the GCAPs. Cones from all four mouse lines showed significant recovery and escaped saturation even in bright background light. This recovery occurred too rapidly to be caused by pigment bleaching or metaII decay and appears to reflect some modulation of response inactivation in addition to those produced by recoverin and the GCAPs. Our experiments now make possible a more detailed understanding of the cellular physiology of mammalian cone photoreceptors and the role of conductances in the inner and outer segment in producing cone light responses.

Download Full-text

PRCD is Concentrated at the Base of Photoreceptor Outer Segments and is Involved in Outer Segment Disc Formation

Human Molecular Genetics ◽

10.1093/hmg/ddz248 ◽

2019 ◽

Cited By ~ 4

Author(s):

Gilad Allon ◽

Irit Mann ◽

Lital Remez ◽

Elisabeth Sehn ◽

Leah Rizel ◽

...

Keyword(s):

Retinal Degeneration ◽

Knockout Mice ◽

Outer Segment ◽

Mouse Retina ◽

Cone Photoreceptors ◽

Photoreceptor Outer Segment ◽

Photoreceptor Outer Segments ◽

Outer Segments ◽

Rod And Cone Photoreceptors ◽

Disc Formation

Abstract Mutations of the PRCD gene are associated with rod-cone degeneration in both dogs and humans. Prcd is expressed in the mouse eye as early as embryonic day 14. In the adult mouse retina PRCD is expressed in the outer segments of both rod and cone photoreceptors. Immunoelectron microscopy revealed that PRCD is located at the outer segment rim, and that it is highly concentrated at the base of the outer segment. Prcd-knockout mice present with progressive retinal degeneration, starting at 20 weeks of age and onwards. This process is reflected by a significant and progressive reduction of both scotopic and photopic electroretinographic responses, and by thinning of the retina, and specifically of the outer nuclear layer, indicating photoreceptor loss. Electron microscopy revealed severe damage to photoreceptor outer segments, which is associated with immigration of microglia cells to the Prcd-knockout retina, and accumulation of vesicles in the inter-photoreceptor space. Phagocytosis of photoreceptor outer segment discs by the retinal pigmented epithelium is severely reduced. Our data show that Prcd-knockout mice serve as a good model for retinal degeneration caused by PRCD mutations in humans. Our findings in these mice support the involvement of PRCD in outer segment disc formation of both rod and cone photoreceptors. Furthermore, they suggest a feedback mechanism which coordinates the rate of photoreceptor outer segment disc formation, shedding and phagocytosis. This study has important implications for understanding the function of PRCD in the retina, as well as for future development of treatment modalities for PRCD-deficiency in humans.

Download Full-text

Migration and synaptogenesis of cone photoreceptors in the developing mouse retina

The Journal of Comparative Neurology ◽

10.1002/(sici)1096-9861(19971110)388:1<47::aid-cne4>3.0.co;2-o ◽

1997 ◽

Vol 388 (1) ◽

pp. 47-63 ◽

Cited By ~ 79

Author(s):

Kathryn A. Rich ◽

Yutian Zhan ◽

Janet C. Blanks

Keyword(s):

Mouse Retina ◽

Cone Photoreceptors

Download Full-text

Residual photosensitivity in mice lacking both rod opsin and cone photoreceptor cyclic nucleotide gated channel 3 α subunit

Visual Neuroscience ◽

10.1017/s0952523804215024 ◽

2004 ◽

Vol 21 (5) ◽

pp. 675-683 ◽

Cited By ~ 17

Author(s):

ALUN R. BARNARD ◽

JOANNE M. APPLEFORD ◽

SUMATHI SEKARAN ◽

KRISHNA CHINTHAPALLI ◽

AARON JENKINS ◽

...

Keyword(s):

Ganglion Cells ◽

Light Exposure ◽

Early Gene ◽

Mouse Retina ◽

Cone Photoreceptors ◽

Light Responses ◽

Α Subunit ◽

Light Reflex ◽

Pupil Light Reflex ◽

Retinal Photoreceptors

The mammalian retina contains three classes of photoreceptor. In addition to the rods and cones, a subset of retinal ganglion cells that express the putative sensory photopigment melanopsin are intrinsically photosensitive. Functional and anatomical studies suggest that these inner retinal photoreceptors provide light information for a number of non-image-forming light responses including photoentrainment of the circadian clock and the pupil light reflex. Here, we employ a newly developed mouse model bearing lesions of both rod and cone phototransduction cascades (Rho−/−Cnga3−/−) to further examine the function of these non-rod non-cone photoreceptors. Calcium imaging confirms the presence of inner retinal photoreceptors inRho−/−Cnga3−/−mice. Moreover, these animals retain a pupil light reflex, photoentrainment, and light induction of the immediate early genec-fosin the suprachiasmatic nuclei, consistent with previous findings that pupillary and circadian responses can employ inner retinal photoreceptors.Rho−/−Cnga3−/−mice also show a light-dependent increase in the number of FOS-positive cells in both the ganglion cell and (particularly) inner nuclear layers of the retina. The average number of cells affected is several times greater than the number of melanopsin-positive cells in the mouse retina, suggesting functional intercellular connections from these inner retinal photoreceptors within the retina. Finally, however, while we show that wild types exhibit an increase in heart rate upon light exposure, this response is absent inRho−/−Cnga3−/−mice. Thus, it seems that non-rod non-cone photoreceptors can drive many, but not all, non-image-forming light responses.

Download Full-text

Local signals in mouse horizontal cell dendrites

10.1101/143909 ◽

2017 ◽

Cited By ~ 1

Author(s):

Camille A. Chapot ◽

Christian Behrens ◽

Luke E. Rogerson ◽

Tom Baden ◽

Sinziana Pop ◽

...

Keyword(s):

Glutamate Release ◽

Horizontal Cell ◽

Horizontal Cells ◽

Single Type ◽

Mouse Retina ◽

Gabaergic Interneuron ◽

List Type ◽

Cone Photoreceptor ◽

Cone Photoreceptors ◽

Temporal Properties

SummaryThe mouse retina contains a single type of horizontal cell, a GABAergic interneuron that samples from all cone photoreceptors within reach and modulates their glutamatergic output via parallel feedback mechanisms. Because horizontal cells form an electrically-coupled network, they have been implicated in global signal processing, such as large scale contrast enhancement. Recently, it has been proposed that horizontal cells can also act locally at the level of individual cone photoreceptors. To test this possibility physiologically, we used two-photon microscopy to record light stimulus-evoked Ca2+signals in cone axon terminals and horizontal cell dendrites as well as glutamate release in the outer plexiform layer. By selectively stimulating the two mouse cone opsins with green and UV light, we assessed whether signals from individual cones remain “isolated” within horizontal cell dendritic tips, or whether they spread across the dendritic arbour. Consistent with the mouse‘s opsin expression gradient, we found that the Ca2+signals recorded from dendrites of dorsal horizontal cells were dominated by M- and those of ventral horizontal cells by S-opsin activation. The signals measured in neighbouring horizontal cell dendritic tips varied markedly in their chromatic preference, arguing against global processing. Rather, our experimental data and results from biophysically realistic modelling support the idea that horizontal cells can process cone input locally, extending the “classical” view of horizontal cells function. Pharmacologically removing horizontal cells from the circuitry reduced the sensitivity of the cone signal to low frequencies, suggesting that local horizontal cell feedback shapes the temporal properties of cone output.HighlightsLight-evoked Ca2+signals in horizontal cell dendrites reflect opsin gradientChromatic preferences in neighbouring dendritic tips vary markedlyMouse horizontal cells process cone photoreceptor input locallyLocal horizontal cell feedback shapes the temporal properties of cone outputeTOC BlurbChapot et al. show that local light responses in mouse horizontal cell dendrites inherit properties, including chromatic preference, from the presynaptic cone photoreceptor, suggesting that their dendrites can provide “private” feedback to cones, for instance, to shape the temporal filtering properties of the cone synapse.

Download Full-text

MicroRNA Signatures of the Developing Primate Fovea

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.654385 ◽

2021 ◽

Vol 9 ◽

Author(s):

Elizabeth S. Fishman ◽

Mikaela Louie ◽

Adam M. Miltner ◽

Simranjeet K. Cheema ◽

Joanna Wong ◽

...

Keyword(s):

Rhesus Monkey ◽

Cell Fate ◽

Molecular Mechanisms ◽

Color Discrimination ◽

Light Sensitivity ◽

Human Vision ◽

Mouse Retina ◽

Mirna Cluster ◽

Cone Photoreceptors ◽

Specialized Region

Rod and cone photoreceptors differ in their shape, photopigment expression, synaptic connection patterns, light sensitivity, and distribution across the retina. Although rods greatly outnumber cones, human vision is mostly dependent on cone photoreceptors since cones are essential for our sharp visual acuity and color discrimination. In humans and other primates, the fovea centralis (fovea), a specialized region of the central retina, contains the highest density of cones. Despite the vast importance of the fovea for human vision, the molecular mechanisms guiding the development of this region are largely unknown. MicroRNAs (miRNAs) are small post-transcriptional regulators known to orchestrate developmental transitions and cell fate specification in the retina. Here, we have characterized the transcriptional landscape of the developing rhesus monkey retina. Our data indicates that non-human primate fovea development is significantly accelerated compared to the equivalent retinal region at the other side of the optic nerve head, as described previously. Notably, we also identify several miRNAs differentially expressed in the presumptive fovea, including miR-15b-5p, miR-342-5p, miR-30b-5p, miR-103-3p, miR-93-5p as well as the miRNA cluster miR-183/-96/-182. Interestingly, miR-342-5p is enriched in the nasal primate retina and in the peripheral developing mouse retina, while miR-15b is enriched in the temporal primate retina and increases over time in the mouse retina in a central-to-periphery gradient. Together our data constitutes the first characterization of the developing rhesus monkey retinal miRNome and provides novel datasets to attain a more comprehensive understanding of foveal development.

Download Full-text