Department of Pathology and Molecular Medicine, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada.
Invest Ophthalmol Vis Sci. 2012 Jun 5;53(7):3316-30. doi: 10.1167/iovs.12-9595.
The signaling pathways and transcriptional effectors responsible for directing mammalian lens development provide key regulatory molecules that can inform our understanding of human eye defects. The hedgehog genes encode extracellular signaling proteins responsible for patterning and tissue formation during embryogenesis. Signal transduction of this pathway is mediated through activation of the transmembrane proteins smoothened and patched, stimulating downstream signaling resulting in the activation or repression of hedgehog target genes. Hedgehog signaling is implicated in eye development, and defects in hedgehog signaling components have been shown to result in defects of the retina, iris, and lens.
We assessed the consequences of constitutive hedgehog signaling in the developing mouse lens using Cre-LoxP technology to express the conditional M2 smoothened allele in the embryonic head and lens ectoderm.
Although initial lens development appeared normal, morphological defects were apparent by E12.5 and became more significant at later stages of embryogenesis. Altered lens morphology correlated with ectopic expression of FoxE3, which encodes a critical gene required for human and mouse lens development. Later, inappropriate expression of the epithelial marker Pax6, and as well as fiber cell markers c-maf and Prox1 also occurred, indicating a failure of appropriate lens fiber cell differentiation accompanied by altered lens cell proliferation and cell death.
Our findings demonstrate that the ectopic activation of downstream effectors of the hedgehog signaling pathway in the mouse lens disrupts normal fiber cell differentiation by a mechanism consistent with a sustained epithelial cellular developmental program driven by FoxE3.
负责指导哺乳动物晶状体发育的信号通路和转录效应因子为我们理解人类眼部缺陷提供了关键的调控分子。Hedgehog 基因编码细胞外信号蛋白，在胚胎发生过程中负责模式形成和组织形成。该途径的信号转导通过跨膜蛋白 smoothened 和 patched 的激活来介导，刺激下游信号转导，导致 Hedgehog 靶基因的激活或抑制。Hedgehog 信号通路与眼睛发育有关，Hedgehog 信号通路成分的缺陷已被证明导致视网膜、虹膜和晶状体的缺陷。
我们使用 Cre-LoxP 技术评估了发育中的小鼠晶状体中组成性 Hedgehog 信号的后果，该技术在胚胎头部和晶状体外胚层中表达条件性 M2 smoothened 等位基因。
尽管初始晶状体发育似乎正常，但在 E12.5 时出现形态缺陷，在胚胎发生的后期阶段变得更加明显。晶状体形态的改变与 FoxE3 的异位表达相关，FoxE3 编码人类和小鼠晶状体发育所必需的关键基因。随后，上皮标志物 Pax6 的表达以及纤维细胞标志物 c-maf 和 Prox1 的表达也发生了异常，表明适当的纤维细胞分化失败，伴随着改变的晶状体细胞增殖和细胞死亡。
我们的发现表明，在小鼠晶状体中异位激活 Hedgehog 信号通路的下游效应物通过一种与 FoxE3 驱动的持续上皮细胞发育程序一致的机制破坏了正常的纤维细胞分化。
