Conditional deletion of AP-2β in the cranial neural crest results in anterior segment dysgenesis and early-onset glaucoma

Abstract

Anterior segment dysgenesis (ASD) encompasses a group of developmental disorders in which a closed angle phenotype in the anterior chamber of the eye can occur and 50% of patients develop glaucoma. Many ASDs are thought to involve an inappropriate patterning and migration of the periocular mesenchyme (POM), which is derived from cranial neural crest cells (NCCs) and mesoderm. Although, the mechanism of this disruption is not well understood, a number of transcriptional regulatory molecules have previously been implicated in ASDs. Here, we investigate the function of the transcription factor AP-2β, encoded by Tfap2b, which is expressed in NCCs and their derivatives. Wnt1-Cre-mediated conditional deletion of Tfap2b in NCCs resulted in post-natal ocular defects typified by opacity. Histological data revealed that the conditional AP-2β NCC knockout (KO) mutants exhibited dysgenesis of multiple structures in the anterior segment of the eye including defects in the corneal endothelium, corneal stroma, ciliary body and disruption in the iridocorneal angle with adherence of the iris to the cornea. We further show that this phenotype leads to a significant increase in intraocular pressure and a subsequent loss of retinal ganglion cells and optic nerve degeneration, features indicative of glaucoma. Overall, our findings demonstrate that AP-2β is required in the POM for normal development of the anterior segment of the eye and that the AP-2β NCC KO mice might serve as a new and exciting model of ASD and glaucoma that is fully penetrant and with early post-natal onset.

Genetic dissection of anterior segment dysgenesis caused by aCol4a1mutation

“…To this end, we crossed the conditional Col4a1 Flex4 1 allele to the Wnt1 Cre line that expresses CRE recombinase in neural crest cells before they migrate from the neural tube. The Wnt1 Cre line has been characterized previously (Danielian et al, 1998) and used in multiple studies (Martino et al, 2016; Iwao et al, 2009; Ittner et al, 2005), and we confirmed the presence of CRE activity in the periocular mesenchyme using a Rosa26 tdTomato reporter line (Madisen et al, 2010) (Fig. 2A,B).…”

Transcriptomic analysis of differential gene expression during chick periocular neural crest differentiation into corneal cells

“…Our data also show upregulation of TFAP2β , which suggests its potential role during chick corneal development. Conditional knockout of TfAp2β in the NCC lineage in mice caused several defects in NCC‐derived ocular tissues including malformation of the corneal endothelium and stroma …”

“…Conditional knockout of TfAp2β in the NCC lineage in mice caused several defects in NCC-derived ocular tissues including malformation of the corneal endothelium and stroma. 32…”

Relationship between neural crest cell specification and rare ocular diseases

“…Follow‐up studies of intraocular pressure measurement demonstrated a threefold increase in adult mutant animals compared to controls, possibly stemming from the aqueous blockade resulting from iridocorneal adhesions. This spike in intraocular pressure corresponded with retinal ganglion cell loss and a reduction in retinal ganglion axon myelination (Martino et al, ). Further work on this mouse model has shown that AP‐2β is important for normal development and morphology of the ciliary body and trabecular meshwork.…”

“…In 2–3 month‐old mutant mice, defects of neural crest‐derived structures were evident, including absence of a corneal endothelium, corneal vascularization, and iridocorneal adhesions. Secondary defects were also observed, including corneolenticular adhesions, with the ciliary body containing fewer folds than control animals (Martino et al, ). Follow‐up studies of intraocular pressure measurement demonstrated a threefold increase in adult mutant animals compared to controls, possibly stemming from the aqueous blockade resulting from iridocorneal adhesions.…”