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Angiopoietin-1 is required for Schlemm’s canal development in mice and humans
Benjamin R. Thomson, … , Terri L. Young, Susan E. Quaggin
Benjamin R. Thomson, … , Terri L. Young, Susan E. Quaggin
Published November 6, 2017
Citation Information: J Clin Invest. 2017;127(12):4421-4436. https://doi.org/10.1172/JCI95545.
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Research Article Ophthalmology Vascular biology Article has an altmetric score of 14

Angiopoietin-1 is required for Schlemm’s canal development in mice and humans

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Abstract

Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm’s canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.

Authors

Benjamin R. Thomson, Tomokazu Souma, Stuart W. Tompson, Tuncer Onay, Krishnakumar Kizhatil, Owen M. Siggs, Liang Feng, Kristina N. Whisenhunt, Tammy L. Yanovitch, Luba Kalaydjieva, Dimitar N. Azmanov, Simone Finzi, Christine E. Tanna, Alex W. Hewitt, David A. Mackey, Yasmin S. Bradfield, Emmanuelle Souzeau, Shari Javadiyan, Janey L. Wiggs, Francesca Pasutto, Xiaorong Liu, Simon W.M. John, Jamie E. Craig, Jing Jin, Terri L. Young, Susan E. Quaggin

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Figure 8

Generation and analysis of Angpt1p.R494* mice.

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Generation and analysis of Angpt1p.R494* mice.
(A) The CRISPR/Cas9 syste...
(A) The CRISPR/Cas9 system was used to generate a novel ANGPT1R494*-expressing mouse line. While Arg-494 is conserved between mice and humans, it is encoded by different codons in each species. Therefore, different genomic DNA modifications are required for the p.R494* substitution in mice and humans. (B) Targeting strategy used to design guide RNAs. (C) Genotyping of N1 mice showing positive mutants following PCR and HpaII digestion. (D) Sanger sequencing analysis of a heterozygous founder mutant. (E) SC appears normal in Angpt1Null/WT and Angpt1p.R494*/WT heterozygous mice. In E, n = 3 WT/WT, 3 Null/WT, and 5 p.R494*/WT (SC area) or 3 (PROX1 expression) animals per group. Scale bars: 50 μm; ×20 fields comprise an area of 65,536 μm2.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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