Loss of ephrin-A5 leads to clinical signs of Peters Anomaly in a mouse model

Peters Anomaly (PA) is the leading cause for corneal transplants in pediatric patients. We investigated whether disruption of Eph-ephrin signaling leads to phenotypes associated with PA, including microphthalmia, cloudy cornea, coloboma, cataract, corneo-lenticular touch (CLT), irido-corneal adhesion (ICA), and persistent fetal vasculature (PFV). Freshly enucleated mouse eyes were imaged under a dissection microscope, and high-resolution confocal images were collected to compare mouse eyes with genetic disruption of EphA2 or ephrin-A5. In ephrin-A5 knockout (KO or ^-/-) eyes, we commonly found microphthalmia, cloudy cornea, coloboma, CLT, ICA, anterior subcapsular cataracts, and PFV; control and EphA2^-/- eyes did not display these phenotypes with significant frequency. Defects in ephrin-A5^-/- eyes were often unilateral, and bilateral defects were not always the same between contralateral eyes. We did not observe premature eye opening in ephrin-A5^-/- mice, and eye defects were present in ephrin-A5^-/- pups at birth, suggesting embryonic development abnormalities. Imaging of tissues from live ephrin-A5^-/- eyes revealed abnormal corneal epithelial cells in deeper corneal layers, shallow anterior chamber, and anterior lens defects due to CLT. Immunostaining demonstrated nerve patterning and epithelial cell defects in ephrin-A5^-/- corneas. This work reveals that Eph-ephrin signaling is needed for separation of the embryonic lens from the cornea during development and nerve patterning in the cornea. Although ephrin-A5 has not been directly linked to PA, this KO model can be utilized for detailed studies of the cellular defects for all clinical signs of PA and suggests that Eph-ephrin signaling is involved in PA.