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

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

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 9

Angpt1p.R494* cannot replace WT Angpt1 in embryonic development.

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Angpt1p.R494* cannot replace WT Angpt1 in embryonic development. (A) He...
(A) Heterozygous Angpt1p.R494*/WT mice were crossed with Angpt1Null/WT animals or inbred with Angpt1p.R494*/WT mice to generate p.R494*/Null or p.R494*/p.R494* offspring completely lacking WT ANGPT1 protein. While Angpt1p.R494*/Null pups were observed at normal Mendelian ratios early in embryonic development, double-mutant and homozygous mutant embryos died between E10.5 and E12.5 and no viable pups were born. (B and C) At E10.5, while all embryos were found alive, some Angpt1p.R494*/Null double mutants appeared smaller than control littermates and exhibited disorganized vasculature. By E12.5, all double-mutant and p.R494* homozygous embryos were found deceased (B and C), and some had been partially reabsorbed. Interestingly, some embryos had a visible hemorrhage in the region of the jugular lymph sac (white arrows), suggesting a possible defect in lymphovenous valve function. †Pups found deceased. *No mortality was observed between birth and P14. Scale bars: 1 mm (B, top panels) and 2 mm (B, bottom panels, and C).