Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
PLoS Genet. 2012;8(11):e1003106. doi: 10.1371/journal.pgen.1003106. Epub 2012 Nov 29.
Mutations in the retinoblastoma tumor suppressor gene (rb1) cause both sporadic and familial forms of childhood retinoblastoma. Despite its clinical relevance, the roles of rb1 during normal retinotectal development and function are not well understood. We have identified mutations in the zebrafish space cadet locus that lead to a premature truncation of the rb1 gene, identical to known mutations in sporadic and familial forms of retinoblastoma. In wild-type embryos, axons of early born retinal ganglion cells (RGC) pioneer the retinotectal tract to guide later born RGC axons. In rb1 deficient embryos, these early born RGCs show a delay in cell cycle exit, causing a transient deficit of differentiated RGCs. As a result, later born mutant RGC axons initially fail to exit the retina, resulting in optic nerve hypoplasia. A significant fraction of mutant RGC axons eventually exit the retina, but then frequently project to the incorrect optic tectum. Although rb1 mutants eventually establish basic retinotectal connectivity, behavioral analysis reveals that mutants exhibit deficits in distinct, visually guided behaviors. Thus, our analysis of zebrafish rb1 mutants reveals a previously unknown yet critical role for rb1 during retinotectal tract development and visual function.
视网膜母细胞瘤肿瘤抑制基因（rb1）的突变导致散发性和家族性儿童视网膜母细胞瘤。尽管它具有临床相关性，但 rb1 在正常视网膜-视顶盖发育和功能中的作用尚不清楚。我们已经在斑马鱼空间学员（space cadet）基因座中鉴定出导致 rb1 基因过早截短的突变，与散发性和家族性视网膜母细胞瘤的已知突变相同。在野生型胚胎中，早期出生的视网膜神经节细胞（RGC）的轴突先驱视网膜-视顶盖投射，引导后来出生的 RGC 轴突。在 rb1 缺陷型胚胎中，这些早期出生的 RGC 表现出细胞周期退出延迟，导致分化的 RGC 暂时缺乏。结果，后来出生的突变型 RGC 轴突最初未能离开视网膜，导致视神经发育不全。突变型 RGC 轴突的很大一部分最终离开视网膜，但随后经常投射到错误的视顶盖。尽管 rb1 突变体最终建立了基本的视网膜-视顶盖连接，但行为分析显示突变体在不同的、视觉引导的行为中存在缺陷。因此，我们对斑马鱼 rb1 突变体的分析揭示了 rb1 在视网膜-视顶盖投射发育和视觉功能中的一个以前未知但至关重要的作用。
