Targeting the vascular-specific phosphatase PTPRB protects against retinal ganglion cell loss in a pre-clinical model of glaucoma.

Benjamin R Thomson,Susan E Quaggin,Dietmar Vestweber,Saily Soman,Tomokazu Souma,Isabel A Carota

doi:10.7554/elife.48474

Benjamin R Thomson, Susan E Quaggin + Show 4 more

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https://doi.org/10.7554/elife.48474

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Elevated intraocular pressure (IOP) due to insufficient aqueous humor outflow through the trabecular meshwork and Schlemm's canal (SC) is the most important risk factor for glaucoma, a leading cause of blindness worldwide. We previously reported loss of function mutations in the receptor tyrosine kinase TEK or its ligand ANGPT1 cause primary congenital glaucoma in humans and mice due to failure of SC development. Here, we describe a novel approach to enhance canal formation in these animals by deleting a single allele of the gene encoding the phosphatase PTPRB during development. Compared to Tek haploinsufficient mice, which exhibit elevated IOP and loss of retinal ganglion cells, Tek+/-;Ptprb+/- mice have elevated TEK phosphorylation, which allows normal SC development and prevents ocular hypertension and RGC loss. These studies provide evidence that PTPRB is an important regulator of TEK signaling in the aqueous humor outflow pathway and identify a new therapeutic target for treatment of glaucoma.

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A leading cause of blindness worldwide, glaucoma is a devastating disease with no cure
Heterozygous PtprbNLS-LacZ/WT mice are born normally (Baumer et al, 2006), expression of PTPRB was reduced by approximately 50% (Figure 1A, uncropped images presented as Figure 1—figure supplement 1)
Reductions in phosphatase abundance had a direct effect on TEK activation and PtprbNLS-LacZ/WT mice showed approximately a 118% increase in phosphorylated TEK when measured in lung tissue using an immunoprecipitation assay (Figure 1B, uncropped images presented as Figure 1—figure supplement 2), confirming our hypothesis that changes in PTPRB expression would have a direct impact on TEK phosphorylation

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Introduction

A leading cause of blindness worldwide, glaucoma is a devastating disease with no cure. Elevated intraocular pressure (IOP) caused by defects in the aqueous humor outflow (AHO) pathway is the most important risk factor for disease progression and vision loss (Coleman and Miglior, 2008; Becker, 1961). IOP reduction is currently the only therapeutic intervention proven to slow glaucoma progression in patients In both humans and mice, the majority of AHO occurs through the conventional route (Johnson et al, 2017; Toris et al, 1999; Toris et al, 2000; Millar et al, 2011; Millar et al, 2015), comprised of the trabecular meshwork (TM) and the large, lymphatic-like Schlemm’s canal (SC) located in the iridocorneal angle (Johnson et al, 2017; Park et al, 2014; Aspelund et al, 2014; Kizhatil et al, 2014). Recent studies have identified the importance of endothelial signaling molecules in development and maintenance of SC and the conventional outflow pathway, and critical roles have been described for the endothelial transcription factor PROX1 (Park et al, 2014) as well as the VEGFR2/3 (Kizhatil et al, 2014; Aspelund et al, 2014) and TEK (Thomson et al, 2014; Kim et al, 2017; Souma et al, 2016; Thomson et al, 2017) receptor tyrosine kinase signaling pathways

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