Abstract
Purpose:
During ocular development, complex patterning events regulate the formation of the neural retina, retinal pigment epithelium (RPE) and anterior eye segment. Interactions with surrounding tissues cause invagination of the optic vesicle, leading to the formation of lens and optic cup that is patterned into the neural retina, the RPE and future ciliary body/iris epithelium. Importantly, the adjacent periocular mesenchyme is critical for RPE and anterior segment development; it expresses the scaffold protein Axin2 that is a universal readout and antagonist of the Wnt/beta-catenin pathway. The purpose of this study is to investigate the role of Axin2 during ocular and extraocular development in mouse.
Methods:
Mice heterozygous and homozygous for a Axin2-lacZ knockin allele were analyzed at different developmental stages for reporter expression, morphology as well as expression of ocular and extraocular markers using histological and immunohistochemical techniques.
Results:
In the developing retina, Axin2-lacZ expression is initiated in ganglion cells at late embryonic stages and in amacrine and horizontal cells postnatally. Activation of the lacZ reporter overlaps with expression of Brn3, Pax6 and calbindin in the postnatatl retina. In the embryo, the reporter is robustly expressed in the periocular mesenchyme, RPE and optic stalk. Global disruption of Axin2 results in upregulation of the reporter and Lef1 expression, another target of the Wnt/beta-catenin pathway, in periocular and ocular tissues. Axin2 knockout mice exhibit variable ocular phenotypes ranging between normal and severely defective eyes with microphthalmia, coloboma and/or expanded ciliary body and iris tissue.
Conclusions:
Our data reveal a critical role of Axin2 during ocular development, possibly by regulating the activity of the Wnt/beta-catenin pathway.
Keywords: 698 retinal development •
533 gene/expression •
714 signal transduction