Unleashing Insights into Glaucoma: A Novel Mouse Model Unveiled by Yap Gene Deregulation.
Uveitic glaucoma-like features in Yap conditional knockout mice Glaucoma is a multifactorial neurodegenerative disease characterized by the progressive and irreversible degeneration of the optic nerve and retinal ganglion cells. Despite medical advances aiming at slowing degeneration, around 40% of treated glaucomatous patients will undergo vision loss. It is thus of utmost importance to have a better understanding of the disease and to investigate more deeply its early causes. The transcriptional coactivator YAP, an important regulator of eye homeostasis, has recently drawn attention in the glaucoma research field.
Here we show that Yap conditional knockout mice (Yap cKO), in which the deletion of Yap is induced in both Müller glia (the only retinal YAP-expressing cells) and the non-pigmented epithelial cells of the ciliary body, exhibit a breakdown of the aqueous-blood barrier, accompanied by a progressive collapse of the ciliary body. A similar phenotype is observed in human samples that we obtained from patients presenting with uveitis. In addition, aged Yap cKO mice harbor glaucoma-like features, including deregulation of key homeostatic Müller-derived proteins, retinal vascular defects, optic nerve degeneration and retinal ganglion cell death. Finally, transcriptomic analysis of Yap cKO retinas pointed to early-deregulated genes involved in extracellular matrix organization potentially underlying the onset and/or progression of the observed phenotype.
Together, our data bring the first experimental evidence pointing to YAP as a key player in glaucoma pathogenesis. They also highlight Yap cKO mice as a preclinical model that might prove useful to elucidate how uveitis may favor glaucoma development, and to investigate in the glaucomatous phase, how glial and vascular perturbations ultimately result in retinal ganglion cell death. Furthermore, this model can offer a new opportunity to test therapeutic approaches targeting this disease.
Uveitic glaucoma-like features in Yap conditional knockout mices. Juliette Bitard, Elodie-Kim Grellier, Sophie Lourdel, Helena Prior Filipe, Annaïg Hamon, François Fenaille, Florence Anne Castelli, Emeline Chu-Van, Jérôme E Roger, Morgane Locker, Muriel Perron
Article published in Cell Death Discovery – Nature – Access to the manuscript
