Zfp503 haploinsufficiency causes optic nerve coloboma in mice.

Abstract

PURPOSE: To investigate the role of Zfp503 in mammalian eye development. METHODS: Zfp503and Zfp503mice were successfully created through the Knockout Mouse Phenotyping Project (KOMP2), and abnormalities were noted through ophthalmic examination. Embryos were studied at E15.5. Postnatal mice were evaluated using electroretinography (ERG), fundus photography, fluorescein angiography, and optical coherence tomography (OCT) to examine phenotypic differences. Hematoxylin and eosin (H&E) staining was performed to evaluate the retina and optic nerve head (ONH) morphology, and immunohistochemistry was used to determine the expression pattern of Zfp503 in the mouse retina and in the human fetal retina. RESULTS: All homozygous Zfp503embryos of both sexes exhibited hypopigmented eyes and/or anophthalmia and were postnatally non-viable. Histopathology showed hypopigmented retinal pigment epithelium (RPE). With H&E staining, homozygote animals showed failure of the optic fissure to close and what appears to be duplicated retinal tissue. All postnatal Zfp503heterozygotes of both sexes displayed an atypical ONH coloboma. Fundus photography of heterozygotes showed a coloboma extending dorsally from the optic nerve head, and an area of abnormal fluorescence in the area associated with the coloboma region was seen on fluorescein angiography. Histopathology and cross-sectional optical coherence tomography (OCT) showed excavation of the ONH. Three-dimensional OCT reconstructions showed an outpouching consistent with coloboma of the ONH. Other systemic abnormalities in homozygous and heterozygous mice were present across both sexes. The human homolog ZNF503 was detected in fetal eyes. CONCLUSIONS: Zfp503 deficiency led to poorly developed RPE and non-viability in Zfp503 knockout mice. Zfp503 heterozygous mice developed an atypical optic nerve coloboma. This study advances previous work by expanding the understanding of the optic nerve coloboma phenotype in heterozygous mice and demonstrating expression of ZNF503 in the developing human eye.