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

Seyyedhassan Paylakhi, Cassandre Labelle-Dumais, Nicholas G. Tolman, Michael A. Sellarole, Yusef Seymens, Joseph Saunders, Hesham Lakosha, Wilhelmine N. deVries, Andrew C. Orr, Piotr Topilko, Simon W.M. John, K. Saidas Nair

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37 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Número de artículoe1007244
PublicaciónPLoS Genetics
Volumen14
N.º3
DOI
EstadoPublished - mar. 2018

Nota bibliográfica

Funding Information:
This work was made possible in part, by NIH-NEI EY002162 - Core Grant for Vision Research, by the Research to Prevent Blindness Unrestricted Grant (UCSF, Ophthalmology) and William and Mary Greve Special Scholar award (KSN), Knight Templar Eye Foundation Career Starter Award (SP), National Eye Institute grants EY022891 (KSN), EY011721 (SWMJ), Barbara and Joseph Cohen Foundation (SWMJ). SWMJ is an investigator of Howard Hughes Medical Institute. Funding support from That Man May See Inc (KSN), Research Evaluation and Allocation Committee (REAC)-Tidemann fund (KSN), Marin Community Foundation- Kathlyn McPherson Masneri and Arno P. Masneri Fund (KSN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We are grateful to Garett Cheung and Eric Dang for assistance with genotyping. We thank Dorenda Itzkowitz for mouse colony management and Suling Wang for assistance with figure preparation. We would also like to thank Yien-Ming Kuo for histological sectioning and staining.

Publisher Copyright:
© 2018 Paylakhi et al.

ASJC Scopus Subject Areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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