Identification of MFRP and the secreted serine proteases PRSS56 and ADAMTS19 as part of a molecular network involved in ocular growth regulation

Precise regulation of ocular size is a critical determinant of normal visual acuity. Although it is generally accepted that ocular growth relies on a cascade of signaling events transmitted from the retina to the sclera, the factors and mechanism(s) involved are poorly understood. Recent studies have highlighted the importance of the retinal secreted serine protease PRSS56 and transmembrane glycoprotein MFRP, a factor predominantly expressed in the retinal pigment epithelium (RPE), in ocular size determination. Mutations in PRSS56 and MFRP constitute a major cause of nanophthalmos, a condition characterized by severe reduction in ocular axial length/extreme hyperopia. Interestingly, common variants of these genes have been implicated in myopia, a condition associated with ocular elongation. Consistent with these findings, mice with loss of function mutation in PRSS56 or MFRP exhibit a reduction in ocular axial length. However, the molecular network and cellular processes involved in PRSS56- and MFRP-mediated ocular axial growth remain elusive. Here, we show that Adamts19 expression is significantly upregulated in the retina of mice lacking either Prss56 or Mfrp. Importantly, using genetic mouse models, we demonstrate that while ADAMTS19 is not required for ocular growth during normal development, its inactivation exacerbates ocular axial length reduction in Prss56 and Mfrp mutant mice. These results suggest that the upregulation of retinal Adamts19 is part of an adaptive molecular response to counteract impaired ocular growth. Using a complementary genetic approach, we show that loss of PRSS56 or MFRP function prevents excessive ocular axial growth in a mouse model of early-onset myopia caused by a null mutation in Irbp, thus, demonstrating that PRSS56 and MFRP are also required for pathological ocular elongation. Collectively, our findings provide new insights into the molecular network involved in ocular axial growth and support a role for molecular crosstalk between the retina and RPE involved in refractive development.

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Identification of ADAMTS19 as a novel retinal factor involved in ocular growth regulation

10.1101/2020.06.03.132852 ◽

2020 ◽

Author(s):

Swanand Koli ◽

Cassandre Labelle-Dumais ◽

Yin Zhao ◽

Seyyedhassan Paylakhi ◽

K Saidas Nair

Keyword(s):

Mouse Models ◽

Axial Length ◽

Growth Regulation ◽

Molecular Response ◽

Refractive Errors ◽

Axial Elongation ◽

Ocular Growth ◽

Genes Encoding ◽

Length Reduction ◽

Axial Growth

ABSTRACTRefractive errors are the most common ocular disorders and are a leading cause of visual impairment worldwide. Although ocular axial length is well established to be a major determinant of refractive errors, the molecular and cellular processes regulating ocular axial growth are poorly understood. Mutations in genes encoding the PRSS56 and MFRP are a major cause of nanophthalmos. Accordingly, mouse models with mutations in the genes encoding the retinal factor PRSS56 or MFRP, a gene predominantly localized in the retinal pigment epithelial (RPE) exhibit ocular axial length reduction and extreme hyperopia. However, the precise mechanisms underlying PRSS56- and MFRP-mediated ocular axial growth remain elusive. Here, we show that Adamts19 expression is significantly upregulated in retina of mice lacking either Prss56 or Mfrp. Using a combination of genetic approaches and mouse models, we show that while ADAMTS19 is not required for ocular growth during normal development, its inactivation exacerbates ocular axial length reduction in both Prss56 or Mfrp mutant mice. These results suggest that the upregulation of retinal Adamts19 expression is part of an adaptive molecular response to counteract impaired ocular growth. Using a complementary genetic approach. We further demonstrate that loss of PRSS56 or MFRP function prevents excessive ocular axial growth in a mouse model of developmental myopia caused by a null mutation in Irpb, demonstrating that ocular axial elongation in Irbp-/- mice is fully dependent on PRSS56 and MFRP functions. Collectively, our findings provide insight into the molecular network involved in ocular axial growth regulation and refractive development and support the notion that relay of the signal between the retina and RPE could be critical for promoting ocular axial elongation.

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Effects of refraction and axial length on the development and progression of diabetic retinopathy

Clinical ophthalmology ◽

10.32364/2311-7729-2021-21-4-205-209 ◽

2021 ◽

Vol 21 (4) ◽

pp. 205-209

Author(s):

M.M. Bikbov ◽

◽

O.I. Orenburkina ◽

A.E. Babushkin ◽

A.A. Fakhretdinova ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Diabetic Retinopathy ◽

Growth Factor ◽

Axial Length ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Vascular Endothelial ◽

Keywords Diabetic Retinopathy ◽

Eye Disorders ◽

Endothelial Growth Factor

Eye disorders have a special place in diabetes since visual impairment has a significant effect on the quality of life. Therefore, determining risk factors and prognostic criteria for disease course are essential for developing strategies for early prevention of diabetic retinopathy (DR). This paper addresses studies on various aspects of DR in patients with myopia. It was demonstrated that DR arises, develops, and progresses in different ways under various axial lengths (AL). Thus, many authors report that DR barely occurs in high myopia. Some of them account for this phenomenon for poor blood circulation in a long myopic eye. Others refer to a significantly lower vascular endothelial growth factor (VEGF) concentration in longer eyes or eyes with myopic refraction. The third authors argue a focal disintegration of retinal pigment epithelium to eliminate metabolic end products through the choroid and sclera. As a result, neither acidosis nor venous congestion develops, and endothelial barrier function remains unaffected Keywords: diabetic retinopathy, myopia, axial length, vascular endothelial growth factor, emmetropia, hyperopia, diabetes. For citation: Bikbov M.M., Orenburkina O.I., Babushkin A.E., Fakhretdinova A.A. Effects of refraction and axial length on the development and progression of diabetic retinopathy. Russian Journal of Clinical Ophthalmology. 2021;21(4):205–209 (in Russ.). DOI: 10.32364/2311-7729- 2021-21-4-205-209.

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The role of bone morphogenetic proteins in the differentiation of the ventral optic cup

Development ◽

10.1242/dev.129.13.3161 ◽

2002 ◽

Vol 129 (13) ◽

pp. 3161-3171 ◽

Cited By ~ 1

Author(s):

Ruben Adler ◽

Teri L. Belecky-Adams

Keyword(s):

Bone Morphogenetic Proteins ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Ectopic Expression ◽

Neural Retina ◽

Optic Disk ◽

Loss Of Function ◽

In Ovo ◽

Optic Stalk ◽

Optic Cup

The ventral region of the chick embryo optic cup undergoes a complex process of differentiation leading to the formation of four different structures: the neural retina, the retinal pigment epithelium (RPE), the optic disk/optic stalk, and the pecten oculi. Signaling molecules such as retinoic acid and sonic hedgehog have been implicated in the regulation of these phenomena. We have now investigated whether the bone morphogenetic proteins (BMPs) also regulate ventral optic cup development. Loss-of-function experiments were carried out in chick embryos in ovo, by intraocular overexpression of noggin, a protein that binds several BMPs and prevents their interactions with their cognate cell surface receptors. At optic vesicle stages of development, this treatment resulted in microphthalmia with concomitant disruption of the developing neural retina, RPE and lens. At optic cup stages, however, noggin overexpression caused colobomas, pecten agenesis, replacement of the ventral RPE by neuroepithelium-like tissue, and ectopic expression of optic stalk markers in the region of the ventral retina and RPE. This was frequently accompanied by abnormal growth of ganglion cell axons, which failed to enter the optic nerve. The data suggest that endogenous BMPs have significant effects on the development of ventral optic cup structures.

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Influence of the foveal curvature on myopic macular complications

Scientific Reports ◽

10.1038/s41598-019-53443-4 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Un Chul Park ◽

Dae Joong Ma ◽

Woon Hyung Ghim ◽

Hyeong Gon Yu

Keyword(s):

Refractive Error ◽

Axial Length ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Cross Sectional Study ◽

Optical Coherence Tomography Image ◽

Cross Sectional ◽

Curvature Index ◽

Tomography Image ◽

And Control

AbstractIn this cross-sectional study, we investigated whether a foveal curvature affects the development of two major myopic macular complications, myopic traction maculopathy (MTM) and myopic choroidal neovascularization (mCNV). In high myopic eyes (axial length ≥ 26.5 mm, refractive error ≤ −6 diopters) with posterior staphyloma, three different parameters of foveal curvature (staphyloma height, coefficient a, and curvature index) calculated based on the retinal pigment epithelium hyperreflective line in spectral domain optical coherence tomography image were compared among the MTM (72 eyes), mCNV (58 eyes), and control (69 eyes) group. The three curvature parameters showed a significant correlation with each other (all P’s < 0.001). The axial length, refractive error, and staphyloma types were comparable among the groups, but the means of all three curvature parameters were significantly greater in the MTM group compared to the mCNV and control groups (all P’s < 0.001). Furthermore, the curvature parameters had a significant correlation with myopic severity in the MTM group, but not in the other groups. These results suggest that a steeper change of foveal curvature plays a role in the development of MTM but not mCNV in high myopes.

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The role of the retinal pigment epithelium in eye growth regulation and myopia: A review

Visual Neuroscience ◽

10.1017/s0952523805223015 ◽

2005 ◽

Vol 22 (3) ◽

pp. 251-261 ◽

Cited By ~ 88

Author(s):

JODI RYMER ◽

CHRISTINE F. WILDSOET

Keyword(s):

Retinal Pigment Epithelium ◽

Growth Regulation ◽

Fluid Transport ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Critical Role ◽

Growth Modulation ◽

Eye Growth ◽

Retinal Growth ◽

Growth Changes

Myopia is increasing in prevalence world-wide, nearing epidemic proportions in some populations. This has led to expanded research efforts to understand how ocular growth and refractive errors are regulated. Eye growth is sensitive to visual experience, and is altered by both form deprivation and optical defocus. In these cases, the primary targets of growth regulation are the choroidal and scleral layers of the eye that demarcate the boundary of the posterior vitreous chamber. Of significance to this review are observations of local growth modulation that imply that the neural retina itself must be the source of growth-regulating signals. Thus the retinal pigment epithelium (RPE), interposed between the retina and the choroid, is likely to play a critical role in relaying retinal growth signals to the choroid and sclera. This review describes the ion transporters and signal receptors found in the chick RPE and their possible roles in visually driven changes in eye growth. We focus on the effects of four signaling molecules, otherwise implicated in eye growth changes (dopamine, acetylcholine, vasoactive intestinal peptide (VIP), and glucagon), on RPE physiology, including fluid transport. A model for RPE-mediated growth regulation is proposed.

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Fallopia Japonica and Prunella Vulgaris Inhibit Myopia Progression by Suppressing Akt and NFκB Mediated Inflammatory Reactions

10.20944/preprints202107.0228.v1 ◽

2021 ◽

Author(s):

Chia-Hung Lin ◽

Chih-Sheng Chen ◽

Yao-Chien Wang ◽

En-Shyh Lin ◽

Ching-Yao Chang ◽

...

Keyword(s):

Transforming Growth Factor Beta ◽

Axial Length ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Retinal Pigment Epithelial Cell ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Myopia Progression ◽

Rpe Cells ◽

Expression Levels

The increased global incidence of myopia requires the establishment of therapeutic approaches. Previous studies have suggested that inflammation plays an important role in the development and progression of myopia. We used human retinal pigment epithelial cell to study the molecular mechanisms on how FJE and PVE lowering the inflammation of the eye. The effect of FJE and PVE in MFD induced hamster model and explore the role of inflammation cytokines in myopia. Expression levels of IL-6, IL-8, and TNF-α were upregulated in retinal pigment epithelium (RPE) cells treated with IL-6 and TNF-α. FJ extract (FJE) + PV extract (PVE) reduced IL-6, IL-8, and TNF-α expression in RPE cells. Furthermore, FJE and PVE inhibited inflammation by attenuating the phosphorylation of protein kinase B (AKT), and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) pathway. In addition, we report two resveratrol + ursolic acid compounds from FJ and PV and their inhibitory activities against IL-6, IL-8, and TNF-α expression levels in RPE cells treated with IL-6 and TNF-α. FJE, PVE, and FJE + PVE were applied to MFD hamsters and their axial length was measured after 21 days. The axial length showed statistically significant differences between phosphate-buffered saline- and FJE-, PVE-, and FJE + PVE-treated MFD eyes. FJE + PVE suppressed expressions of IL-6, IL-8, and TNF-α. They also inhibited myopia-related transforming growth factor-beta (TGF)-β1, matrix metalloproteinase (MMP)-2, and NF-κB expression while increasing type Ⅰ collagen expression. Overall, these results suggest that FJE + PVE may have a therapeutic effect on myopia and be used as a potential treatment option.

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Co-Injection of Sulfotyrosine Facilitates Retinal Uptake of Hyaluronic Acid Nanospheres Following Intravitreal Injection

Pharmaceutics ◽

10.3390/pharmaceutics13091510 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1510

Author(s):

Aiden Eblimit ◽

Mustafa S. Makia ◽

Daniel Strayve ◽

Ryan Crane ◽

Shannon M. Conley ◽

...

Keyword(s):

Hyaluronic Acid ◽

Retinal Pigment Epithelium ◽

Intravitreal Injection ◽

Targeted Delivery ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Mouse Retina ◽

Loss Of Function ◽

Outer Retina ◽

Fluorescent Reporters

Gene and drug delivery to the retina is a critical therapeutic goal. While the majority of inherited forms of retinal degeneration affect the outer retina, specifically the photoreceptors and retinal pigment epithelium, effective targeted delivery to this region requires invasive subretinal delivery. Our goal in this work was to evaluate two innovative approaches for increasing both the persistence of delivered nanospheres and their penetration into the outer retina while using the much less invasive intravitreal delivery method. We formulated novel hyaluronic acid nanospheres (HA-NS, 250 nm and 500 nm in diameter) conjugated to fluorescent reporters and delivered them intravitreally to the adult Balb/C mouse retina. They exhibited persistence in the vitreous and along the inner limiting membrane (ILM) for up to 30 days (longest timepoint examined) but little retinal penetration. We thus evaluated the ability of the small molecule, sulfotyrosine, to disrupt the ILM, and found that 3.2 µg/µL sulfotyrosine led to significant improvement in delivery to the outer retina following intravitreal injections without causing retinal inflammation, degeneration, or loss of function. Co-delivery of sulfotyrosine and HA-NS led to robust improvements in penetration of HA-NS into the retina and accumulation along the interface between the photoreceptors and the retinal pigment epithelium. These exciting findings suggest that sulfotyrosine and HA-NS may be an effective strategy for outer retinal targeting after intravitreal injection.

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Ocular-Component-Specific miRNA Expression in a Murine Model of Lens-Induced Myopia

International Journal of Molecular Sciences ◽

10.3390/ijms20153629 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3629 ◽

Cited By ~ 1

Author(s):

Tanaka ◽

Kurihara ◽

Hagiwara ◽

Ikeda ◽

Mori ◽

...

Keyword(s):

Mirna Expression ◽

Axial Length ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Expression Ratio ◽

Mirna Microarray ◽

Three Samples ◽

Differentially Expressed Mirnas ◽

Refractive Change ◽

Ocular Components

To identify tissues and molecules involved in refractive myopic shift and axial length elongation in a murine lens-induced myopia model, we performed a comprehensive analysis of microRNA (miRNA) expression. Three weeks after negative 30 diopter lens fixation on three-week-old C57BL/6J mice, total RNA was extracted from individual ocular components including cornea, iris, lens, retina, retinal pigment epithelium (RPE)/choroid, and sclera tissue. The miRNA expression analysis was pooled from three samples and carried out using Agilent Mouse miRNA Microarray (8 × 60 K) miRBase21.0. The expression ratio was calculated, and differentially expressed miRNAs were extracted, using GeneSpring GX 14.5. Myopic induction showed a significant myopic refractive change, axial elongation, and choroidal thinning. Through the comprehensive miRNA analysis, several upregulated miRNAs (56 in cornea tissue, 13 in iris tissue, 6 in lens tissue, 0 in retina tissue, 29 in RPE/choroid tissue, and 30 in sclera tissue) and downregulated miRNAs (7 in cornea tissue, 28 in iris tissue, 17 in lens tissue, 9 in retina tissue, 7 in RPE/choroid tissue, and 40 in sclera tissue) were observed. Overlapping expression changes in miRNAs were also found in different ocular components. Some of this miRNA dysregulation may be functionally involved in refractive myopia shift and axial length elongation.

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Distinct expression requirements and rescue strategies for BEST1 loss- and gain-of-function mutations

eLife ◽

10.7554/elife.67622 ◽

2021 ◽

Vol 10 ◽

Author(s):

Qingqing Zhao ◽

Yang Kong ◽

Alec Kittredge ◽

Yao Li ◽

Yin Shen ◽

...

Keyword(s):

Pigment Epithelium ◽

Retinal Pigment ◽

Genetic Mutation ◽

Dominant Negative ◽

Loss Of Function ◽

Gain Of Function ◽

Rpe Cells ◽

Degenerative Disorders ◽

Universal Treatment ◽

Human Rpe Cells

Genetic mutation of the human BEST1 gene, which encodes a Ca2+-activated Cl- channel (BEST1) predominantly expressed in retinal pigment epithelium (RPE), causes a spectrum of retinal degenerative disorders commonly known as bestrophinopathies. Previously, we showed that BEST1 plays an indispensable role in generating Ca2+-dependent Cl- currents in human RPE cells, and the deficiency of BEST1 function in patient-derived RPE is rescuable by gene augmentation (Li et al., 2017). Here, we report that BEST1 patient-derived loss-of-function and gain-of-function mutations require different mutant to wild-type (WT) molecule ratios for phenotypic manifestation, underlying their distinct epigenetic requirements in bestrophinopathy development, and suggesting that some of the previously classified autosomal dominant mutations actually behave in a dominant-negative manner. Importantly, the strong dominant effect of BEST1 gain-of-function mutations prohibits the restoration of BEST1-dependent Cl- currents in RPE cells by gene augmentation, in contrast to the efficient rescue of loss-of-function mutations via the same approach. Moreover, we demonstrate that gain-of-function mutations are rescuable by a combination of gene augmentation with CRISPR/Cas9-mediated knockdown of endogenous BEST1 expression, providing a universal treatment strategy for all bestrophinopathy patients regardless of their mutation types.

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Prevalence of and factors associated with dilated choroidal vessels beneath the retinal pigment epithelium among the Japanese

Scientific Reports ◽

10.1038/s41598-021-90493-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yasuki Ito ◽

Mari Ito ◽

Takeshi Iwase ◽

Keiko Kataoka ◽

Kazuhisa Yamada ◽

...

Keyword(s):

Risk Factors ◽

Retinal Pigment Epithelium ◽

Axial Length ◽

Choroidal Thickness ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Younger Age ◽

Male Sex ◽

Associated Risk Factors ◽

Choroidal Vessels

AbstractPachyvessels are pathologically dilated large choroidal vessels and are associated with the pathogenesis of several pachychoroid-related disorders, including central serous chorioretinopathy. We aimed to investigate the prevalence of and risk factors for pachyvessels in the Japanese population. We included 316 participants (aged ≥ 40 years) with normal right eyes. The presence of pachyvessels (vertical diameter > 300 µm, distance to the retinal pigment epithelium < 50 µm) was determined using 6 × 6 mm macular swept-source optical coherence tomography images, and associated risk factors were investigated. Subfoveal choroidal thickness was measured, and its associated risk factors investigated. The overall prevalence of pachychoroids was 9.5%. Regression analysis showed that a younger age, shorter axial length, male sex, and smoking were significantly associated with the presence of pachyvessels (p = 0.047; odds ratio [OR] 0.96 per year, p = 0.021; OR 0.61 per 1 mm, p = 0.012; OR 3.08 vs. female, and p = 0.011; OR 3.15 vs. non-smoker, respectively) and greater choroidal thickness (p < 0.001, p < 0.001, p < 0.003, and p < 0.017, respectively). The results were consistent with other research findings which showed that pachychoroid-related disorders such as central serous chorioretinopathy were associated with younger age, male sex, shorter axial length, and smoking. Smoking may be associated with choroidal circulatory disturbance in the Japanese population.

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