Targeting the vascular-specific phosphatase PTPRB protects against retinal ganglion cell loss in a pre-clinical model of glaucoma
- Northwestern University, United States
- 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
Benjamin R Thomson
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
- Lois Smith, Boston Children's Hospital/Harvard Medical School, United States
Publication history
- Received: May 15, 2019
- Accepted: October 11, 2019
- Accepted Manuscript published: October 17, 2019 (version 1)
- 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.
Metrics
-
- 1,408
- Page views
-
- 248
- Downloads
-
- 12
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Developmental Biology
- Neuroscience
Mutations in the RNA helicase, DDX3X, are a leading cause of Intellectual Disability and present as DDX3X syndrome, a neurodevelopmental disorder associated with cortical malformations and autism. Yet, the cellular and molecular mechanisms by which DDX3X controls cortical development are largely unknown. Here, using a mouse model of Ddx3x loss-of-function we demonstrate that DDX3X directs translational and cell cycle control of neural progenitors, which underlies precise corticogenesis. First, we show brain development is sensitive to Ddx3x dosage; complete Ddx3x loss from neural progenitors causes microcephaly in females, whereas hemizygous males and heterozygous females show reduced neurogenesis without marked microcephaly. In addition, Ddx3x loss is sexually dimorphic, as its paralog, Ddx3y, compensates for Ddx3x in the developing male neocortex. Using live imaging of progenitors, we show that DDX3X promotes neuronal generation by regulating both cell cycle duration and neurogenic divisions. Finally, we use ribosome profiling in vivo to discover the repertoire of translated transcripts in neural progenitors, including those which are DDX3X-dependent and essential for neurogenesis. Our study reveals invaluable new insights into the etiology of DDX3X syndrome, implicating dysregulated progenitor cell cycle dynamics and translation as pathogenic mechanisms.
-
- Developmental Biology
- Evolutionary Biology
Whereas no known living vertebrate possesses gills derived from the jaw-forming mandibular arch, it has been proposed that the jaw arose through modifications of an ancestral mandibular gill. Here, we show that the zebrafish pseudobranch, which regulates blood pressure in the eye, develops from mandibular arch mesenchyme and first pouch epithelia and shares gene expression, enhancer utilization, and developmental gata3 dependence with the gills. Combined with work in chondrichthyans, our findings in a teleost fish point to the presence of a mandibular pseudobranch with serial homology to gills in the last common ancestor of jawed vertebrates, consistent with a gill origin of vertebrate jaws.
