This Title All WIREs
How to cite this WIREs title:
Impact Factor: 9.957

RNA‐binding proteins in eye development and disease: implication of conserved RNA granule components

Full article on Wiley Online Library:   HTML PDF

Can't access this content? Tell your librarian.

The molecular biology of metazoan eye development is an area of intense investigation. These efforts have led to the surprising recognition that although insect and vertebrate eyes have dramatically different structures, the orthologs or family members of several conserved transcription and signaling regulators such as Pax6, Six3, Prox1, and Bmp4 are commonly required for their development. In contrast, our understanding of posttranscriptional regulation in eye development and disease, particularly regarding the function of RNA‐binding proteins (RBPs), is limited. We examine the present knowledge of RBPs in eye development in the insect model Drosophila as well as several vertebrate models such as fish, frog, chicken, and mouse. Interestingly, of the 42 RBPs that have been investigated for their expression or function in vertebrate eye development, 24 (~60%) are recognized in eukaryotic cells as components of RNA granules such as processing bodies, stress granules, or other specialized ribonucleoprotein (RNP) complexes. We discuss the distinct developmental and cellular events that may necessitate potential RBP/RNA granule‐associated RNA regulon models to facilitate posttranscriptional control of gene expression in eye morphogenesis. In support of these hypotheses, three RBPs and RNP/RNA granule components Tdrd7, Caprin2, and Stau2 are linked to ocular developmental defects such as congenital cataract, Peters anomaly, and microphthalmia in human patients or animal models. We conclude by discussing the utility of interdisciplinary approaches such as the bioinformatics tool iSyTE (integrated Systems Tool for Eye gene discovery) to prioritize RBPs for deriving posttranscriptional regulatory networks in eye development and disease. WIREs RNA 2016, 7:527–557. doi: 10.1002/wrna.1355 This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development
Control of the eukaryotic mRNA by RNA‐binding proteins (RBPs). RBPs function in distinct regulatory events in the mRNA life cycle. During transcription of a gene to pre‐mRNA, the nascent transcript is capped with 7‐methylguanosine to stabilize the mRNA, a process that is facilitated by RBPs such as RAM. RBPs bind to the 5′‐cap to form the cap‐binding complex and mediate further control. Excision of the intronic regions from the pre‐mRNA can occur co‐transcriptionally, a process in which RBPs can bind to the splicing machinery or the exon–intron junctions to drive tissue‐specific splicing reactions. The 3′ end of the pre‐mRNA is cleaved at a specific site followed by addition of 150–200 adenosine residues [poly(A) tail] to form a mature mRNA, a process that is facilitated by RBPs such as poly(A)‐binding protein (Pabp). The mature mRNA is then bound by specialized RBPs and exported to the cytosol. In the cytosol, binding of RBPs (e.g., Stau1 or Zbp1) to either the 3′‐UTR or the 5′‐UTR facilitates the localization of mRNA to specific regions for site‐specific translation in cells such as neurons or fibroblasts. The localized mRNA is either stabilized or degraded by RBPs binding to sequence‐specific sites such as the ARE (AU‐rich element) in its 3′ UTR. Within the cytosol, RBPs facilitate translation of mRNA into polypeptide. Alternately, mRNA can be recruited to RNA granules such as processing bodies (P‐bodies), stress granules, or other ribonucleoprotein (RNP) complexes for stability, localized translation, silencing, or decay (not shown).
[ Normal View | Magnified View ]
Conservation of regulatory factors in metazoan eye development. Comparison of signaling molecules, transcription factors, and RBPs in Drosophila and vertebrate eye development. RBPs shown in magenta color are orthologs or protein family members of fly proteins that are expressed in the vertebrate eye and need to be investigated in detail.
[ Normal View | Magnified View ]
Mouse lens development events that may involve RBP function. (a) Specific cellular and differentiation events in lens development where RBP‐mediated posttranscriptional regulation may occur are outlined. (b) Potential function of Caprin2 in the separation of lens pit from the overlying surface ectoderm (future cornea) is outlined. p63 protein is expressed in cells that will contribute to the cornea. It is abruptly absent in adjacent cells that separate out from the surface ectoderm and associate together to form the anterior epithelium of the lens vesicle. The absence of p63 in these cells coincides with enriched Caprin2 granular staining, suggesting a potential relationship that may be the topic of future investigations.
[ Normal View | Magnified View ]
Processing bodies in mouse lens and retina development. (a–a″) The processing body (P‐body) marker Dcp1a is observed to stain distinct granules in the mouse lens at embryonic day (E) 12.5. P‐bodies are RNA granules that undertake mRNA storage, decay, or silencing. (b–b″) A second P‐body marker, Ddx6, stains distinct granules and co‐localizes with Dcp1a in the mouse lens epithelial cell line 17EM15. (c–e″) P‐body markers Ddx6 and Dcp1a stain distinct granules and co‐localize in the E12.5 mouse retina. Scale bar in a, e is 25 µm; in a′, b″, e′, e″ is 10 µm; in a″ is 5 µm.
[ Normal View | Magnified View ]
Tdrd7 and Stau1 granules in mouse lens development. (a) Tdrd7 protein is localized to cytoplasmic granules in lens fiber cells of mouse at embryonic day (E) 12.5. (a′) Broken line denoted area in ‘a’ is shown at high magnification. Deficiency of Tdrd7, a Lotus/OST‐HTH and tudor domain protein and RNA granule (RG) component, in human and mouse causes cataracts and glaucoma. (b) Stau1 cytoplasmic granules are observed in lens fiber cells at E12.5. (b′) Broken line denoted area in ‘b’ is shown at high magnification. Stau1 (Staufen 1), a double‐stranded RBP and RG component, functions in the localization of mRNA in oocytes and neurons. Scale bar in a, b is 25 µm; in a′, b′ is 5 µm.
[ Normal View | Magnified View ]
Eye development in Drosophila. (a) In the third larval stage of Drosophila development, Hedgehog (Hh) and Decapentaplegic (Dpp) signaling initiates eye development. The signaling results in the formation of a morphogenetic furrow in the epithelium that moves toward the anterior end. New ommatidia are formed posterior to the morphogenetic furrow. The movement of the furrow is inversely related to development of the ommatidia. (b) Each adult ommatidium consists of a biconvex corneal lens, a pseudocone, eight photoreceptors (R1–R8), and four non‐neuronal cone cells.
[ Normal View | Magnified View ]
Phenotypic characteristics of the developing mouse eye. Representative embryonic and postnatal mouse eye tissue stained with hematoxylin and eosin stains that bind to nucleic acid‐ and protein‐rich regions in the cell, respectively, are shown in (a–e). Immunofluorescence maker analyses of key genes in mouse lens development are shown in (f–j). (a) At E11.5, a hollow lens vesicle is observed, in which posteriorly located cells have initiated differentiation into primary fiber cells. Also observed is the retina that is primarily composed of the retinal progenitor and ganglion cells. (b) At E13.5, the lumen of the lens vesicle is filled with elongated primary fiber cells and the epithelial cells can be seen in the anterior region of the lens. The overlying surface ectoderm will form the cornea. (c) At age 2 months, an adult lens exhibits an epithelial cell layer at the anterior region and fiber cells in the posterior region. The cornea has several layers of cells and the retina is developed with a laminated structure. (d) High magnification image of a postnatal day (P) 14 mouse lens. In the transition zone, cells of the anterior epithelium exit the cell cycle and initiate differentiation of fiber cells. Single head broken arrow indicates direction of early to mature differentiating fiber cells, while double head arrow indicates direction of fiber cell elongation. Terminally differentiated mature fiber cells form a central nuclear‐free region called the organelle‐free zone in the lens. (e) Adult mouse retina is a laminated structure comprising of 11 distinct layers of cells. The sclera originates from the neural ectoderm and protects the eye globe. (f) At E10.5, a critical regulator of eye development Pax6 exhibits expression and nuclear localization in cells of the lens pit and the optic cup. (g) At E11.5, Pax6 continues to be expressed in the lens vesicle and in the retina. (h) A lens‐enriched transcription factor Foxe3 is expressed in the lens pit at E10.5. (i) At E11.5, Foxe3 is expressed in all the cells of the lens vesicle. (j) In the following stages, Foxe3 protein is restricted to the cells of the anterior epithelium of the lens. γ‐Crystallin is a marker for differentiated lens fiber cells. Abbreviations: LV, lens vesicle; R, retina; AEL, anterior epithelium of the lens; C, cornea; FC, fiber cells; TZ, transition zone; OFZ, organelle‐free zone; Ant., anterior; Post., posterior; ILM, inner limiting membrane; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; ELM, external limiting membrane; LRC, layer of rods and cones; RPE, retinal pigment epithelium; CHO, choroid; SC, sclera; OC, optic cup; LP, lens pit. Scale bar in a, b, i, j is 100 µm; c is 400 µm.
[ Normal View | Magnified View ]
Eye development in vertebrates. (a) During gastrulation, the ectoderm is divided into three distinct regions—neural ectoderm, non‐neural ectoderm, and the border ectoderm region between these tissues. (b) The border ectoderm gives rise to pre‐placodal ectoderm and neural crest cells. Red dotted rectangle indicates a section through the embryo that is represented in (c). (c) The neural ectoderm cells comprising the neural plate fold inward to form the neural tube. (d) A region of cells within the neural ectoderm (anterior neural plate) is specified by eye field transcription factors to form a single eye field, which by Sonic Hedgehog signaling, is partitioned into bilateral optic sulci. (e) Each of the optic sulci develops into an optic vesicle that migrates toward the non‐neural ectoderm, which is specified as the surface ectoderm or pre‐placodal ectoderm. (f) Interactions between the optic vesicle and the pre‐placodal ectoderm result into the latter forming the lens placode. The surrounding periocular mesenchyme inhibits the surface ectoderm that does not appose the optic vesicle from acquiring lens fate. (g) Subsequently, the lens placode and the optic vesicle coordinately invaginate to form the lens pit and optic cup, respectively. (h) The lens pit continues to invaginate with the optic cup until it pinches off to form the lens, while the overlying surface ectoderm contributes toward the cornea. The optic cup forms the neuro‐retina and the retinal pigment epithelium (RPE). (i) Subsequent development and differentiation results in the formation of a multicomponent eye. In the anterior region, the adult eye contains the outer cornea, the iris, the lens, the ciliary body, and ciliary zonules, while in the posterior region, it contains the retina. The space between the cornea and the lens is occupied by aqueous humor, while that between the lens and the retina is occupied by the vitreous humor. Light is focused by the cornea and the lens on the retina. The iris responds to the intensity of the light and changes its pinhole similar to the aperture of a camera. The focusing power of the lens is mediated by the ciliary zonules, arising from the ciliary body. Photoreceptor cells within the retina convert the photon energy in light into electrical signals that are transmitted by the optic nerve to the brain where it is interpreted as an image. The RPE has several functions such as light absorption, nutrient transport, and reduction of photooxidative stress by photoreceptor membrane renewal. The fovea is a location in the retina where there is a high concentration of cone photoreceptor cells and where visual sharpness is high.
[ Normal View | Magnified View ]

Related Articles

The role of posttranslational modifications in the assembly of stress granules
The evolution of vision (WIREs WIREs Developmental Biology)
Building the developmental oculome: systems biology in vertebrate eye development and disease (WIREs WIREs Systems Biology and Medicine)

Browse by Topic

RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA in Disease and Development > RNA in Disease
RNA in Disease and Development > RNA in Development

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts