PAX6 disease models for aniridia

Abstract

Aniridia is a pan-ocular genetic developmental eye disorder characterized by complete or partial iris and foveal hypoplasia, for which there is no treatment currently. Progressive sight loss can arise from cataracts, glaucoma, and aniridia-related keratopathy, which can be managed conservatively or through surgical intervention. The vast majority of patients harbor heterozygous mutations involving the PAX6 gene, which is considered the master transcription factor of early eye development. Over the past decades, several disease models have been investigated to gain a better understanding of the molecular pathophysiology, including several mouse and zebrafish strains and, more recently, human-induced pluripotent stem cells (hiPSCs) derived from aniridia patients. The latter provides a more faithful cellular system to study early human eye development. This review outlines the main aniridia-related animal and cellular models used to study aniridia and highlights the key discoveries that are bringing us closer to a therapy for patients.

Keywords: Aniridia; LESC; PAX6; hiPSC; primary cells; retinal organoids; sey mouse; zebrafish.

Figure 1

(a) Right anterior segment showing complete iris hypoplasia. (b) Color fundus photograph lacking foveal reflex and (c) Spectral domain optical coherence tomography (SD-OCT) of the right macula showing complete foveal hypoplasia. (d) Pax6^Sey/+ mouse H and E whole eye sections at postnatal (p) day 60 (top) showing a small eye, lens, and retinal dysplasia, and a thinned P14 corneal epithelium (bottom). (e) Brightfield images (top) and toluidine blue-stained sections (bottom) displaying anterior segment dysgenesis (black arrow), small eye and lens (le) (white arrow), and thickened cornea (co) in 5dpf pax6bSa15822 zebrafish mutant. dpf = days post-fertilization, H and E = hematoxylin and eosin, re = retina

Figure 2

(a) Human, mouse, and zebrafish PAX6 gene structure (boxes show exons and colors correspond to the respective protein domain as shown in b). (b) The two main PAX6 isoforms in humans. The DNA-binding domains PD and HD are illustrated. CTS = C-terminal subdomain, EE = ectodermal enhancer, HD = homeodomain, LNK = linker region, NTS = N-terminal subdomain, P0, P1, Pα = promoters (blue boxes) and regulatory elements (parallelograms), PD = paired domain, PSTD = proline–serine–threonine domain