Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
Cell Rep. 2022 Feb 1;38(5):110312. doi: 10.1016/j.celrep.2022.110312.
The Zic family of zinc finger transcription factors plays a critical role in multiple developmental processes. Using loss-of-function studies, we find that Zic5 is important for the differentiation of retinal pigmented epithelium (RPE) and the rod photoreceptor layer through suppressing Hedgehog (Hh) signaling. Further, Zic5 interacts with the critical Hh signaling molecule, Gli3, through the zinc finger domains of both proteins. This Zic5-Gli3 interaction disrupts Gli3/Gli3 homodimerization, resulting in Gli3 protein stabilization via a reduction in Gli3 ubiquitination. During embryonic Hh signaling, the activator form of Gli is normally converted to a repressor form through proteosome-mediated processing of Gli3, and the ratio of Gli3 repressor to full-length (activator) form of Gli3 determines the Gli3 repressor output required for normal eye development. Our results suggest Zic5 is a critical player in regulating Gli3 stability for the proper differentiation of RPE and rod photoreceptor layer during Xenopus eye development.
锌指转录因子家族在多种发育过程中起着关键作用。通过功能丧失研究，我们发现 Zic5 通过抑制 Hedgehog（Hh）信号通路对视网膜色素上皮（RPE）和杆状光感受器层的分化很重要。此外，Zic5 通过两种蛋白质的锌指结构域与关键的 Hh 信号分子 Gli3 相互作用。这种 Zic5-Gli3 相互作用破坏了 Gli3/Gli3 同源二聚体的形成，导致 Gli3 蛋白稳定性增加，因为 Gli3 的泛素化减少。在胚胎期 Hh 信号转导过程中，Gli 的激活形式通常通过蛋白酶体介导的 Gli3 加工转化为抑制形式，而 Gli3 抑制剂与全长（激活）形式的比例决定了正常眼发育所需的 Gli3 抑制剂输出。我们的研究结果表明，在非洲爪蟾眼睛发育过程中，Zic5 是调节 Gli3 稳定性的关键因素，对于 RPE 和杆状光感受器层的正常分化至关重要。
