Babcock Holly E, Dutta Sunit, Alur Ramakrishna P, Brocker Chad, Vasiliou Vasilis, Vitale Susan, Abu-Asab Mones, Brooks Brian P
Unit on Pediatric, Developmental and Genetic Ophthalmology, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, United States of America.
PLoS One. 2014 Jul 8;9(7):e101782. doi: 10.1371/journal.pone.0101782. eCollection 2014.
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.
葡萄膜缺损是一种潜在致盲的先天性眼部畸形，由发育过程中视裂未能闭合引起。尽管已描述了众多基因的突变，但这些仅占少数病例，使得分子诊断和遗传咨询变得复杂。在此，我们描述了醛脱氢酶7A1（aldh7a1）作为正常眼睛发育所必需基因的关键作用。我们表明，在斑马鱼中通过吗啉代寡核苷酸敲低aldh7a1会导致葡萄膜缺损以及nlz1（另一个已知的导致缺损表型的因素）的调控异常，以及骨骼异常。敲低aldh7a1会导致斑马鱼视杯中的细胞增殖减少，延迟视裂边缘的靠近。通过共注射nlz1 mRNA可部分挽救aldh7a1吗啉代寡核苷酸注射胚胎的表型，这表明在调节视杯中的细胞增殖方面，nlz1在功能上位于aldh7a1的下游。这些结果支持了aldh7a1在斑马鱼眼部发育和骨骼异常中的作用。
