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

  1. Benjamin R Thomson
  2. Isabel A Carota
  3. Tomokazu Souma
  4. Saily Soman
  5. Dietmar Vestweber
  6. Susan E Quaggin  Is a corresponding author
  1. Northwestern University, United States
  2. Max Planck Institute for Molecular Biomedicine, Germany

Abstract

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.

Data availability

All data described have been included in the manuscript. No data sets were generated during the course of this study.

Article and author information

Author details

  1. Benjamin R Thomson

    Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6565-5866
  2. Isabel A Carota

    Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    Isabel A Carota, was employed by Eli Lilly and Company during the time of study completion and manuscript preparation.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7980-2377
  3. Tomokazu Souma

    Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3285-8613
  4. Saily Soman

    Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    No competing interests declared.
  5. Dietmar Vestweber

    Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Competing interests
    Dietmar Vestweber, is a scientific advisory board member of Aerpio Pharmaceuticals.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3517-732X
  6. Susan E Quaggin

    Feinberg School of Medicine, Northwestern University, Chicago, United States
    For correspondence
    quaggin@northwestern.edu
    Competing interests
    Susan E Quaggin, has applied for patents related to therapeutic targeting of the ANGPT-TEK pathway in ocular hypertension and glaucoma and receives research support, owns stock in and is a director of Mannin Research.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3706-5727

Funding

National Institutes of Health (R01 HL124120)

  • Susan E Quaggin

National Institutes of Health (R01 EY025799)

  • Susan E Quaggin

National Institutes of Health (P30 DK114857)

  • Susan E Quaggin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and the ARVO guidelines for care and use of vertebrate research subjects in eye research. All animal experiments were approved by the Animal Care Committee at the Center for Comparative Medicine of Northwestern University (Evanston, Illinois, USA) under animal protocols IS00002777, IS00006571 and IS00003091.

Reviewing Editor

  1. Lois Smith, Boston Children's Hospital/Harvard Medical School, United States

Publication history

  1. Received: May 15, 2019
  2. Accepted: October 11, 2019
  3. Accepted Manuscript published: October 17, 2019 (version 1)
  4. Version of Record published: November 22, 2019 (version 2)

Copyright

© 2019, Thomson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Benjamin R Thomson
  2. Isabel A Carota
  3. Tomokazu Souma
  4. Saily Soman
  5. Dietmar Vestweber
  6. Susan E Quaggin
(2019)
Targeting the vascular-specific phosphatase PTPRB protects against retinal ganglion cell loss in a pre-clinical model of glaucoma
eLife 8:e48474.
https://doi.org/10.7554/eLife.48474

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