Deletion of transcription factor AP-2β from the developing murine trabecular meshwork region leads to progressive glaucomatous changes.

Autor: Taiyab A; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada., Akula M; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada., Dham J; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada., Deschamps P; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada., Sheardown H; Department of Chemical Engineering, McMaster University, Hamilton, ON, Canada., Williams T; Department of Craniofacial Biology, University of Colorado, Aurora, CO, USA., Borrás T; Department of Ophthalmology, University of North Carolina School of Medicine, Chapel Hill, NC, USA., West-Mays JA; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
Jazyk: angličtina
Zdroj: Journal of neuroscience research [J Neurosci Res] 2022 Feb; Vol. 100 (2), pp. 638-652. Date of Electronic Publication: 2021 Nov 25.
DOI: 10.1002/jnr.24982
Abstrakt: Glaucoma is one of the leading causes of irreversible blindness and can result from abnormalities in anterior segment structures required for aqueous humor outflow, including the trabecular meshwork (TM) and Schlemm's canal (SC). Transcription factors such as AP-2β play critical roles in anterior segment development. Here, we show that the Mgp-Cre knock-in (Mgp-Cre.KI) mouse can be used to target the embryonic periocular mesenchyme giving rise to the TM and SC. Fate mapping of male and female mice indicates that AP-2β loss causes a decrease in iridocorneal angle cells derived from Mgp-Cre.KI-expressing populations compared to controls. Moreover, histological analyses revealed peripheral iridocorneal adhesions in AP-2β mutants that were accompanied by a decrease in expression of TM and SC markers, as observed using immunohistochemistry. In addition, rebound tonometry showed significantly higher intraocular pressure (IOP) that was correlated with a progressive significant loss of retinal ganglion cells, reduced retinal thickness, and reduced retinal function, as measured using an electroretinogram, in AP-2β mutants compared with controls, reflecting pathology described in late-stage glaucoma patients. Importantly, elevated IOP in AP-2β mutants was significantly reduced by treatment with latanoprost, a prostaglandin analog that increases unconventional outflow. These findings demonstrate that AP-2β is critical for TM and SC development, and that these mutant mice can serve as a model for understanding and treating progressive human primary angle-closure glaucoma.
(© 2021 Wiley Periodicals LLC.)
Databáze: MEDLINE
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