Müller 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.

Prss56 expression in the rodent hypothalamus: Inverse correlation with pro‐opiomelanocortin suggests oscillatory gene expression in adult rat tanycytes

“…Interestingly, periodic oscillatory gene expression is common during development in mammalian stem cells and neural progenitor cells (Imayoshi & Kageyama, ; Roese‐Koerner, Stappert, & Brustle, ; Shimojo & Kageyama, ; Suzuki, Furusawa, & Kaneko, ; William et al, ), and tanycytes are now recognized as adult neural stem and progenitor cells because they can self‐renew and also differentiate into neurons or astrocytes (Chaker et al, ; Haan et al, ; Lee et al, ; Robins et al, ; Xu et al, ). Thus, periodic gene expression in tanycytes may be a characteristic related specifically to their stem/progenitor cell properties, which is also supported by the fact that Prss56 is specific to stem or progenitor cells in the brain, retina and skin (Gresset et al, ; Jourdon et al, ; Paylakhi et al, ).…”

“…Previous studies also noted the juxtaposition of tanycyte processes and tanycyte‐derived cells (Robins et al, ; Xu et al, ). We hypothesize that Prss56, being a membrane‐bound or secreted protease, may facilitate the migration of these cells by degrading extracellular matrix proteins and/or disrupting cell adhesion molecules on the cell surface (Nair et al, ; Paylakhi et al, ). It is also of interest that parenchymal Prss56 ‐expressing cells were often found as adjacent pairs, or sometimes as multiple adjacent cells, suggesting that two or more Prss56 ‐expressing tanycytes migrate together into the parenchyma and/or some of these cells divide while in the parenchyma.…”

PRSS56 is required for the developmental positioning of ocular angle structures

“…Consistent with observations in patients, we have recently shown that Prss56 mutant mice exhibit reduced ocular axial length and develop an ocular phenotype resembling ACG 14 . Of note, their lens diameter is indistinguishable from that of the control eyes, causing the lens to occupy a relatively larger volume in Prss56 mutant eyes 14,15 . We have previously proposed that these anatomical features could contribute to the ocular angle closure phenotype and IOP elevation observed in Prss56 mutant mice 14 .…”

“…We have recently demonstrated that mice homozygous for a null allele of Prss56 (Prss56 -/-) 15 exhibit ocular axial length reduction, an anatomical feature predisposing to ACG ( Fig. 1A).…”

“…Although specific anatomical features are well established to predispose to ACG, they are generally not sufficient to induce angle closure/high IOP and other contributing factors remain largely unknown 11 . We have previously demonstrated that mutations in the gene coding for the secreted serine protease PRSS56 result in severe reduction in ocular axial length (nanophthalmos) in humans and many of these individuals go on to develop ACG [14][15][16] . Consistent with observations in patients, we have recently shown that Prss56 mutant mice exhibit reduced ocular axial length and develop an ocular phenotype resembling ACG 14 .…”