Wholemount imaging reveals abnormalities of the aqueous outflow pathway and corneal vascularity in Foxc1 and Bmp4 heterozygous mice

Merwe, E.L. van der; Kidson, Susan H.

doi:10.1016/j.exer.2016.04.003

Cited by 5 publications

(6 citation statements)

References 26 publications

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“…Elsewhere in the body, disruptions in this relationship lead to defects in vascular development and play a central role in diseases ranging from diabetic retinopathy to kidney disease and cancer 51 . Several well-characterized EC-mural signaling pathways, including the angiopoietin, VEGF 4 , 5 , 52 , TGFB 53 and BMP 54 , 55 pathways have been linked to glaucoma or elevated IOP in humans and animal models. These findings suggest that signaling interactions between SC and nearby supporting cells are essential for IOP homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Cellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies

et al. 2021

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Primary congenital glaucoma (PCG) is a severe disease characterized by developmental defects in the trabecular meshwork (TM) and Schlemm’s canal (SC), comprising the conventional aqueous humor outflow pathway of the eye. Recently, heterozygous loss of function variants in TEK and ANGPT1 or compound variants in TEK/SVEP1 were identified in children with PCG. Moreover, common variants in ANGPT1and SVEP1 have been identified as risk alleles for primary open angle glaucoma (POAG) in GWAS studies. Here, we show tissue-specific deletion of Angpt1 or Svep1 from the TM causes PCG in mice with severe defects in the adjacent SC. Single-cell transcriptomic analysis of normal and glaucomatous Angpt1 deficient eyes allowed us to identify distinct TM and SC cell populations and discover additional TM-SC signaling pathways. Furthermore, confirming the importance of angiopoietin signaling in SC, delivery of a recombinant ANGPT1-mimetic promotes developmental SC expansion in healthy and Angpt1 deficient eyes, blunts intraocular pressure (IOP) elevation and RGC loss in a mouse model of PCG and lowers IOP in healthy adult mice. Our data highlight the central role of ANGPT1-TEK signaling and TM-SC crosstalk in IOP homeostasis and provide new candidates for SC-targeted glaucoma therapy.

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Section: Discussionmentioning

confidence: 99%

Cellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies

et al. 2021

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“…Several groups have associated aberrant BMP4 activity with ASD phenotypes [ 10 , 12 , 35 ]. However, the spatiotemporal requirements of BMP4 for the morphogenesis of specific anterior segment structures are unknown.…”

Section: Resultsmentioning

confidence: 99%

“…Since no anterior or posterior segment abnormalities were observed in the conditional mutants, we are confident that the developmental ASD and retinal defects detected in Bmp4 haploinsufficient mice on the C57BL/6J background are not due to the loss of optic cup neuroepithelium-derived BMP4. Interestingly, Van der Merwe & Kidson showed that nearly half of the Bmp4 heterozygous null mice they examined on an ICR background (a strain absent from Chang and colleagues’ study) displayed missing portions of Schlemm’s canal [ 35 ], suggesting that ASD phenotypes caused by Bmp4 mutations are not exclusive to C57BL/6J mice. The identification of strain-dependent phenotypic penetrance, as well as possible genetic modifiers of BMP4, requires additional study.…”

Section: Discussionmentioning

confidence: 99%

Ciliary margin-derived BMP4 does not have a major role in ocular development

2018

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Heterozygous Bmp4 mutations in humans and mice cause severe ocular anterior segment dysgenesis (ASD). Abnormalities include pupil displacement, corneal opacity, iridocorneal adhesions, and variable intraocular pressure, as well as some retinal and vascular defects. It is presently not known what source of BMP4 is responsible for these defects, as BMP4 is expressed in several developing ocular and surrounding tissues. In particular, BMP4 is expressed in the ciliary margins of the optic cup which give rise to anterior segment structures such as the ciliary body and iris, making it a good candidate for the required source of BMP4 for anterior segment development. Here, we test whether ciliary margin-derived BMP4 is required for ocular development using two different conditional knockout approaches. In addition, we compared the conditional deletion phenotypes with Bmp4 heterozygous null mice. Morphological, molecular, and functional assays were performed on adult mutant mice, including histology, immunohistochemistry, in vivo imaging, and intraocular pressure measurements. Surprisingly, in contrast to Bmp4 heterozygous mutants, our analyses revealed that the anterior and posterior segments of Bmp4 conditional knockouts developed normally. These results indicate that ciliary margin-derived BMP4 does not have a major role in ocular development, although subtle alterations could not be ruled out. Furthermore, we demonstrated that the anterior and posterior phenotypes observed in Bmp4 heterozygous animals showed a strong propensity to co-occur, suggesting a common, non-cell autonomous source for these defects.

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“…Mutations in some of the commonly associated genes with glaucoma, namely CYP1B1 12 , FOXC1 13 , PITX2 14 , and TEK 15 have been shown to be associated with developmental abnormalities in the outflow pathways in experimental studies. The severity of angle dysgenesis has been correlated on histopathology with certain CYP1B1 gene mutations in All rights reserved.…”

Section: Introductionmentioning

confidence: 99%

Deep learning based models to study the effect of glaucoma genes on angle dysgenesis in-vivo

Gupta

Birla

Varshney

et al. 2021

Preprint

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Objective: To predict the presence of Angle Dysgenesis on Anterior Segment Optical Coherence Tomography (ADoA) using deep learning and to correlate ADoA with mutations in known glaucoma genes. Design: A cross-sectional observational study. Participants: Eight hundred, high definition anterior segment optical coherence tomography (ASOCT) B-scans were included, out of which 340 images (One scan per eye) were used to build the machine learning (ML) model and the rest were used for validation of ADoA. Out of 340 images, 170 scans included PCG (n=27), JOAG (n=86) and POAG (n=57) eyes and the rest were controls. The genetic validation dataset consisted of another 393 images of patients with known mutations compared with 320 images of healthy controls Methods: ADoA was defined as the absence of Schlemm's canal(SC), the presence of extensive hyper-reflectivity over the region of trabecular meshwork or a hyper-reflective membrane (HM) over the region of the trabecular meshwork. Deep learning was used to classify a given ASOCT image as either having angle dysgenesis or not. ADoA was then specifically looked for, on ASOCT images of patients with mutations in the known genes for glaucoma (MYOC, CYP1B1, FOXC1 and LTBP2). Main Outcome measures: Using Deep learning to identify ADoA in patients with known gene mutations. Results: Our three optimized deep learning models showed an accuracy > 95%, specificity >97% and sensitivity >96% in detecting angle dysgenesis on ASOCT in the internal test dataset. The area under receiver operating characteristic (AUROC) curve, based on the external validation cohort were 0.91 (95% CI, 0.88 to 0.95), 0.80 (95% CI, 0.75 to 0.86) and 0.86 (95% CI, 0.80 to 0.91) for the three models. Amongst the patients with known gene mutations, ADoA was observed among all the patients with MYOC mutations, as it was also observed among those with CYP1B1, FOXC1 and with LTBP2 mutations compared to only 5% of those healthy controls (with no glaucoma mutations). Conclusions: Three deep learning models were developed for a consensus-based outcome to objectively identify ADoA among glaucoma patients. All patients with MYOC mutations had ADoA as predicted by the models.

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Wholemount imaging reveals abnormalities of the aqueous outflow pathway and corneal vascularity in Foxc1 and Bmp4 heterozygous mice

Cited by 5 publications

References 26 publications

Cellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies

Cellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies

Ciliary margin-derived BMP4 does not have a major role in ocular development

Deep learning based models to study the effect of glaucoma genes on angle dysgenesis in-vivo

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