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Deletion of transcription factor AP‐2β from the developing murine trabecular meshwork region leads to progressive glaucomatous changes
Author(s) -
Taiyab Aftab,
Akula Monica,
Dham Japnit,
Deschamps Paula,
Sheardown Heather,
Williams Trevor,
Borrás Teresa,
WestMays Judith A.
Publication year - 2022
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.24982
Subject(s) - trabecular meshwork , glaucoma , intraocular pressure , retinal , ophthalmology , myocilin , retinal degeneration , retinal ganglion cell , biology , chemistry , anatomy , medicine
Abstract 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.