Abstract
Uveal coloboma is a potentially blinding congenital ocular malformation caused by failure of the optic fissure to close during development. Although mutations in numerous genes have been described, these account for a minority of cases, complicating molecular diagnosis and genetic counseling. Here we describe a key role of aldh7a1 as a gene necessary for normal eye development. We show that morpholino knockdown of aldh7a1 in zebrafish causes uveal coloboma and misregulation of nlz1, another known contributor to the coloboma phenotype, as well as skeletal abnormalities. Knockdown of aldh7a1 leads to reduced cell proliferation in the optic cup of zebrafish, delaying the approximation of the edges of the optic fissure. The aldh7a1 morphant phenotype is partially rescued by co-injection of nlz1 mRNA suggesting that nlz1 is functionally downstream of aldh7a1 in regulating cell proliferation in the optic cup. These results support a role of aldh7a1 in ocular development and skeletal abnormalities in zebrafish.
Highlights
Development of the mammalian eye begins with an evagination of forebrain neuroepithelium, which undergoes subsequent invagination to form a dual-layered optic cup
Knockdown of aldh7a1 by Aldh7a1 MO1in zebrafish embryos resulted in bent tail (Figure S3A, D in File S1); coloboma of the eye evident at 28 hpf which persists until at least 5–6 days post-fertilization (Figure 2B,D; Figure S3 E,F in File S1) compared to control embryos (Figure 2A,C; Figure S3B,C in File S1) where the optic fissure had nearly fused at 28 hpf (Figure 2A)
Co-injection of Aldh7a1 MO1 and Aldh7a1 MO2 resulted in coloboma (Figure S3 I, J in File S1), but with lower total concentrations of MO compared to controls (Figure S3 G,H in File S1)
Summary
Development of the mammalian eye begins with an evagination of forebrain neuroepithelium (the optic vesicle), which undergoes subsequent invagination to form a dual-layered optic cup. This invagination is asymmetric, such that a ventral opening (the optic fissure) forms around the fifth week of human gestation. If the process of optic fissure closure is faulty, a uveal coloboma—a potentially blinding congenital ocular malformation—results [1,2]. This condition can affect the iris, retina, choroid, retinal pigment epithelium (RPE), and/or the optic nerve. Coloboma patients have displayed mutations in more than twenty developmentally-regulated genes (reviewed in [11]). These genes, account for a minority of patients, implying that other genes may be involved in the pathogenesis of coloboma and that uveal coloboma is a complex trait involving the action of many genes in concert [10,12,13]
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