Vision relies on two types of photoreceptor cells, rods and cones. Rods outnumber cones in the retinas of humans and most other vertebrate species, yet the contribution of cones to our vision is far ...more impactful than rods. A new study reveals an elegant enzymatic mechanism that favors light perception by cones under daylight conditions when rods are saturated by light and contribute little to useful vision.
Vision relies on two types of photoreceptor cells, rods and cones. Rods outnumber cones in the retinas of humans and most other vertebrate species, yet the contribution of cones to our vision is far more impactful than rods. A new study reveals an elegant enzymatic mechanism that favors light perception by cones under daylight conditions when rods are saturated by light and contribute little to useful vision.
For decades, photoreceptors have been an outstanding model system for elucidating basic principles in sensory transduction and biochemistry and for understanding many facets of neuronal cell biology. ...In recent years, new knowledge of the kinetics of signaling and the large-scale movements of proteins underlying signaling has led to a deeper appreciation of the photoreceptor's unique challenge in mediating the first steps in vision over a wide range of light intensities.
Microglia from different nervous system regions are molecularly and anatomically distinct, but whether they also have different functions is unknown. We combined lineage tracing, single-cell ...transcriptomics, and electrophysiology of the mouse retina and showed that adult retinal microglia shared a common developmental lineage and were long-lived but resided in two distinct niches. Microglia in these niches differed in their interleukin-34 dependency and functional contribution to visual-information processing. During certain retinal-degeneration models, microglia from both pools relocated to the subretinal space, an inducible disease-associated niche that was poorly accessible to monocyte-derived cells. This microglial transition involved transcriptional reprogramming of microglia, characterized by reduced expression of homeostatic checkpoint genes and upregulation of injury-responsive genes. This transition was associated with protection of the retinal pigmented epithelium from damage caused by disease. Together, our data demonstrate that microglial function varies by retinal niche, thereby shedding light on the significance of microglia heterogeneity.
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•Retina has 2 microglia pools differing by niche and IL-34 dependency•In homeostasis, IL-34-dependent microglia contribute to neuronal function•In degeneration, both pools relocate toward the retinal pigmented epithelium (RPE)•This transition reprograms microglia and is associated with RPE protection
Whether microglia that reside in different central nervous system niches have distinct functions is unclear. O’Koren and Yu et al. now reveal key functional differences in microglia across two anatomically distinct locations in the retina during homeostasis. Furthermore, in degenerative conditions, microglia migrate to another location where they undergo transcriptional reprogramming and contribute to retinal cytoprotection.
Photoreceptor discs are membrane organelles harboring components of the visual signal transduction pathway. The mechanism by which discs form remains enigmatic and is the subject of a major ...controversy. Classical studies suggest that discs are formed as serial plasma membrane evaginations, whereas a recent alternative postulates that discs, at least in mammalian rods, are formed through intracellular vesicular fusion. We evaluated these models in mouse rods using methods that distinguish between the intracellular vesicular structures and plasma membrane folds independently of their appearance in electron micrographs. The first differentiated membranes exposed to the extracellular space from intracellular membranes; the second interrogated the orientation of protein molecules in new discs. Both approaches revealed that new discs are plasma membrane evaginations. We further demonstrated that vesiculation and plasma membrane enclosure at the site of new disc formation are artifacts of tissue fixation. These data indicate that all vertebrate photoreceptors use the evolutionary conserved membrane evagination mechanism to build their discs.
Inherited retinal degenerations, affecting more than 2 million people worldwide, are caused by mutations in over 200 genes. This suggests that the most efficient therapeutic strategies would be ...mutation independent, i.e., targeting common pathological conditions arising from many disease-causing mutations. Previous studies revealed that one such condition is an insufficiency of the ubiquitin-proteasome system to process misfolded or mistargeted proteins in affected photoreceptor cells. We now report that retinal degeneration in mice can be significantly delayed by increasing photoreceptor proteasomal activity. The largest effect is observed upon overexpression of the 11S proteasome cap subunit, PA28α, which enhanced ubiquitin-independent protein degradation in photoreceptors. Applying this strategy to mice bearing one copy of the P23H rhodopsin mutant, a mutation frequently encountered in human patients, quadruples the number of surviving photoreceptors in the inferior retina of 6-month-old mice. This striking therapeutic effect demonstrates that proteasomes are an attractive target for fighting inherited blindness.
Genes encoding cell-surface proteins control nervous system development and are implicated in neurological disorders. These genes produce alternative mRNA isoforms which remain poorly characterized, ...impeding understanding of how disease-associated mutations cause pathology. Here we introduce a strategy to define complete portfolios of full-length isoforms encoded by individual genes. Applying this approach to neural cell-surface molecules, we identify thousands of unannotated isoforms expressed in retina and brain. By mass spectrometry we confirm expression of newly-discovered proteins on the cell surface in vivo. Remarkably, we discover that the major isoform of a retinal degeneration gene, CRB1, was previously overlooked. This CRB1 isoform is the only one expressed by photoreceptors, the affected cells in CRB1 disease. Using mouse mutants, we identify a function for this isoform at photoreceptor-glial junctions and demonstrate that loss of this isoform accelerates photoreceptor death. Therefore, our isoform identification strategy enables discovery of new gene functions relevant to disease.
Photoreceptor Discs: Built Like Ectosomes Spencer, William J.; Lewis, Tylor R.; Pearring, Jillian N. ...
Trends in cell biology,
11/2020, Letnik:
30, Številka:
11
Journal Article
Recenzirano
Odprti dostop
The light-sensitive outer segment organelle of the vertebrate photoreceptor cell is a modified cilium filled with hundreds of flattened ‘disc’ membranes that provide vast light-absorbing surfaces. ...The outer segment is constantly renewed with new discs added at its base every day. This continuous process is essential for photoreceptor viability. In this review, we describe recent breakthroughs in the understanding of disc morphogenesis, with a focus on the molecular mechanisms responsible for initiating disc formation from the ciliary membrane. We highlight the discoveries that this mechanism evolved from an innate ciliary process of releasing small extracellular vesicles, or ectosomes, and that both disc formation and ectosome release rely on the actin cytoskeleton.
Light-capturing ‘disc’ membranes of vertebrate photoreceptor cells are formed as serial evaginations of the ciliary membrane.Many primary cilia release extracellular vesicles called ‘ectosomes.’The photoreceptor cilium also has an innate ability to release ectosomes, but they are retained by the photoreceptor-specific protein peripherin-2. Retained ectosomes are transformed into discs through membrane flattening, expansion, and enclosure.Both ciliary ectosomes and photoreceptor discs rely on branched actin networks nucleated by the Arp2/3 complex for their formation.
Vision is the most fundamental of our senses initiated when photons are absorbed by the rod and cone photoreceptor neurons of the retina. At the distal end of each photoreceptor resides a ...light-sensing organelle, called the outer segment, which is a modified primary cilium highly enriched with proteins involved in visual signal transduction. At the proximal end, each photoreceptor has a synaptic terminal, which connects this cell to the downstream neurons for further processing of the visual information. Understanding the mechanisms involved in creating and maintaining functional compartmentalization of photoreceptor cells remains among the most fascinating topics in ocular cell biology. This review will discuss how photoreceptor compartmentalization is supported by protein sorting, targeting and trafficking, with an emphasis on the best-studied cases of outer segment-resident proteins.
Dark and light adaptation of retinal neurons allow our vision to operate over an enormous light intensity range. Here we report a mechanism that controls the light sensitivity and operational range ...of rod-driven bipolar cells that mediate dim-light vision. Our data indicate that the light responses of these cells are enhanced by sustained chloride currents via GABA
C receptor channels. This sensitizing GABAergic input is controlled by dopamine D1 receptors, with horizontal cells serving as a plausible source of GABA release. Our findings expand the role of dopamine in vision from its well-established function of suppressing rod-driven signals in bright light to enhancing the same signals under dim illumination. They further reveal a role for GABA in sensitizing the circuitry for dim-light vision, thereby complementing GABA's traditional role in providing dynamic feedforward and feedback inhibition in the retina.
► The sensitivity of rod-driven vision is regulated by dopamine and GABA ► The effect of dopamine is conveyed via D1 receptors ► Dopamine stimulates sustained GABAergic input onto rod bipolar cells ► GABA sensitizes rod bipolar cells via GABA
C receptors
For over 30 years, photoreceptors have been an outstanding model system for elucidating basic principles in sensory transduction and G protein signaling. Recently, photoreceptors have become an ...equally attractive model for studying many facets of neuronal cell biology. The primary goal of this review is to illustrate this rapidly growing trend. We will highlight the areas of active research in photoreceptor biology that reveal how different specialized compartments of the cell cooperate in fulfilling its overall function: converting photon absorption into changes in neurotransmitter release. The same trend brings us closer to understanding how defects in photoreceptor signaling can lead to cell death and retinal degeneration.
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