Abstract
Purpose:
Anterior segment dysgenesis (ASD) encompasses a group of developmental disorders in which a closed angle phenotype 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 (NCC) and mesoderm. However, the mechanism of this disruption is not well understood. We tested the hypothesis that conditional deletion of the Tfap2b gene, encoding Activating Protein-2β (AP-2β), in the neural crest cell (NCC) population of the eye will lead to dysgenesis of the anterior segment, disruption in aqueous humour outflow and ultimately glaucomatous optic neuropathy.
Methods:
AP-2β null mice die soon after birth precluding a detailed analysis of postnatal ocular development. To circumvent this a conditional knockout of AP-2β in the NCC population in the eye was created by breeding Wnt1-Cre transgenic mice with AP-2β “floxed” mice. Eyes were enucleated from AP-2β conditional mutants (AP-2β NCC KO) (n=8) and their wild-type littermates (n=4) at six-weeks, formalin-fixed, embedded in paraffin and sectioned at 4μm. Sections were examined using light and immunofluorescent microscopy.
Results:
Histological data revealed that the AP-2β NCC 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 iridiocorneal angle with adherence of the iris to the cornea. In addition, loss of retinal ganglion cells was observed alongside increased retinal glial activity, confirmed with anti-Brn3a and anti-GFAP staining respectively.
Conclusions:
These data support the hypothesis that expression of AP-2β in the NCC- derived POM of the eye was necessary for normal development and formation of anterior segment tissues. Furthermore, the resulting dysgenesis led to glaucomatous features, suggesting that the AP-2β NCC KO mouse mutants may serve as a novel model of ASD and glaucoma with an early post-natal onset.