Dataset Information

Muller glia-derived PRSS56 is required to sustain ocular axial growth and prevent refractive error.

ABSTRACT: A mismatch between optical power and ocular axial length results in refractive errors. Uncorrected refractive errors constitute the most common cause of vision loss and second leading cause of blindness worldwide. Although the retina is known to play a critical role in regulating ocular growth and refractive development, the precise factors and mechanisms involved are poorly defined. We have previously identified a role for the secreted serine protease PRSS56 in ocular size determination and PRSS56 variants have been implicated in the etiology of both hyperopia and myopia, highlighting its importance in refractive development. Here, we use a combination of genetic mouse models to demonstrate that Prss56 mutations leading to reduced ocular size and hyperopia act via a loss of function mechanism. Using a conditional gene targeting strategy, we show that PRSS56 derived from Müller glia contributes to ocular growth, implicating a new retinal cell type in ocular size determination. Importantly, we demonstrate that persistent activity of PRSS56 is required during distinct developmental stages spanning the pre- and post-eye opening periods to ensure optimal ocular growth. Thus, our mouse data provide evidence for the existence of a molecule contributing to both the prenatal and postnatal stages of human ocular growth. Finally, we demonstrate that genetic inactivation of Prss56 rescues axial elongation in a mouse model of myopia caused by a null mutation in Egr1. Overall, our findings identify PRSS56 as a potential therapeutic target for modulating ocular growth aimed at preventing or slowing down myopia, which is reaching epidemic proportions.

SUBMITTER: Paylakhi S

PROVIDER: S-EPMC5864079 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Müller glia-derived PRSS56 is required to sustain ocular axial growth and prevent refractive error.

Paylakhi Seyyedhassan S Labelle-Dumais Cassandre C Tolman Nicholas G NG Sellarole Michael A MA Seymens Yusef Y Saunders Joseph J Lakosha Hesham H deVries Wilhelmine N WN Orr Andrew C AC Topilko Piotr P John Simon Wm SW Nair K Saidas KS

PLoS genetics 20180312 3

A mismatch between optical power and ocular axial length results in refractive errors. Uncorrected refractive errors constitute the most common cause of vision loss and second leading cause of blindness worldwide. Although the retina is known to play a critical role in regulating ocular growth and refractive development, the precise factors and mechanisms involved are poorly defined. We have previously identified a role for the secreted serine protease PRSS56 in ocular size determination and PRS ...[more]

PMID: 29529029

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Project description:Importance:Uncorrected refractive error (RE) is a leading cause of visual impairment, and variations in ocular anatomy determine RE. The unique ocular determinants of RE in Chinese American individuals have not been studied previously. Objective:To report ocular determinants of RE in a Chinese American population 50 years and older in Monterey Park, California. Design, Setting, and Participants:The Chinese American Eye Study, a population-based, cross-sectional study, was conducted from February 1, 2010, through October 31, 2013, in Monterey Park, with this particular data analysis performed from January 1 through December 31, 2016. This study included data from 4582 participants who underwent an eye examination to obtain axial length (AL), central corneal thickness, vitreous chamber depth (VCD), anterior chamber depth (ACD), lens thickness (LT), corneal power (CP), noncycloplegic subjective refraction, and lens nuclear opalescence (NOP) grading. Data from the right phakic eye of each participant were used. Multiple regression models (standardized regression coefficients [SRCs] and semipartial correlation coefficients squared [SPCCs2]) identified key determinants of RE. Main Outcomes and Measures:Ocular determinants of RE. Results:Among the 4071 participants eligible for analysis (1496 men [36.7%] and 2575 women [63.3%]; mean [SD] age, 60.5 [8.1] years), mean (SD) RE was -0.52 (2.95) diopters (D), with no sex-related difference. A hyperopic shift occurred in women from -0.62 (2.95) D at 50 to 59 years to 0.60 (1.62) D at 80 years or older and in men from -0.69 (3.00) D at 50 to 59 years to 0.40 (2.29) D at 80 years or older (P < .001 for both). Compared with men, women had shorter AL (mean [SD], 23.62 [1.34] vs 24.14 [1.27] mm; P = .006), shorter ACD (mean [SD], 3.33 [0.34] vs 3.44 [0.34] mm; P < .001), and steeper CP (mean [SD], 43.50 [1.52] vs 42.88 [1.45] D; P = .02), after adjusting for age and height. No sex differences were found in VCD, LT, and NOP after height adjustment. Compared with younger individuals, older individuals had shallower ACD, thicker LT, and more NOP compared with younger individuals (P < .001 for both), even after adjustment for height. Axial length was the strongest determinant of RE (SRC = -0.92; SPCC2 = 0.55), followed by CP (SRC = -0.43; SPCC2 = 0.15). When individual components of AL were evaluated, VCD had the greatest contributing effect (SRC = -0.99; SPCC2 = 0.52), followed by CP (SRC = -0.47; SPCC2 = 0.15) and LT (SRC = -0.29; SPCC2 = 0.06). Conclusions and Relevance:These data suggest that Chinese American individuals have longer AL and greater contribution of AL to RE than do Latino and other Chinese populations. Future studies should explore risk factors for increased AL in Chinese Americans and potential interventions that may ultimately prevent myopia-related disease.

Dataset Information

Muller glia-derived PRSS56 is required to sustain ocular axial growth and prevent refractive error.

Publications

Müller glia-derived PRSS56 is required to sustain ocular axial growth and prevent refractive error.

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