Neurobiology Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, MD 20892, USA.
Hum Mol Genet. 2012 Apr 15;21(8):1848-60. doi: 10.1093/hmg/ddr616. Epub 2012 Jan 6.
Nineteen Wnt ligands and 10 Frizzled (Fz) receptors mediate multiple distinct cellular events during neuronal development. However, their precise roles in cell-type specification and organogenesis are poorly delineated because of overlapping functions and expression profiles. Here, we have explored the role of two closely related Frizzled receptors, Fz5 and Fz8, in mouse retinal development. We previously showed that Fz5(-/-) mice exhibit mild coloboma and microphthalmia at ~50% penetrance. Fz8 expression overlaps with Fz5 in the neural retina and optic fissure/disc. Mice lacking Fz8 show minimal eye and retinal defects. The embryos lacking both Fz5 and Fz8 die early in development, but a majority of triallelic Fz5(-/-);Fz8(+/-) mutants survive until birth. The triallelic mutant develops severe retinal coloboma and microphthalmia with full penetrance. At the cellular level, impaired neurogenesis is indicated by increased early-born retinal neurons that result from accelerated cell cycle exit of progenitors. Deficiency of apical retinal neuroepithelium is indicated by altered localization of apical junction markers, such as atypical protein kinase C, RhoA and β-catenin. Hes1 expression, which is critical for retinal progenitor expansion, is down-regulated in the triallelic mutant mouse. Furthermore, blocking Frizzled receptors in cultured retinal explants led to basally shifted divisions of retinal progenitors. Together, our studies suggest a dose-dependent regulation of signaling by Fz5 and Fz8 in optic fissure/disc formation and progenitor expansion.
19 种 Wnt 配体和 10 种卷曲（Fz）受体在神经元发育过程中介导多种不同的细胞事件。然而，由于功能和表达谱重叠，它们在细胞类型特化和器官发生中的精确作用仍不清楚。在这里，我们研究了两个密切相关的卷曲受体 Fz5 和 Fz8 在小鼠视网膜发育中的作用。我们之前的研究表明，Fz5(-/-) 小鼠在 50%的情况下表现出轻度的视窝和小眼畸形。Fz8 的表达与神经视网膜和视裂/盘的 Fz5 重叠。缺乏 Fz8 的小鼠表现出最小的眼睛和视网膜缺陷。缺乏 Fz5 和 Fz8 的胚胎在发育早期死亡，但大多数三等位基因 Fz5(-/-);Fz8(+/-) 突变体可以存活到出生。三等位基因突变体表现出严重的视网膜视窝和小眼畸形，具有完全的外显率。在细胞水平上，神经发生受损的迹象是早期出生的视网膜神经元增加，这是由于祖细胞的细胞周期退出加速所致。视网膜神经上皮的顶端缺陷表现在顶端连接标记物如非典型蛋白激酶 C、RhoA 和 β-连环蛋白的定位改变。Hes1 的表达对于视网膜祖细胞的扩增至关重要，在三等位基因突变体小鼠中下调。此外，在培养的视网膜外植体中阻断卷曲受体导致视网膜祖细胞的基底分裂。总之，我们的研究表明，Fz5 和 Fz8 对视裂/盘形成和祖细胞扩增的信号具有剂量依赖性调节作用。
