Zic5 stabilizes Gli3 via a non-transcriptional mechanism during retinal development

• Published in: Cell reports (Cambridge) 2022-02, Vol.38 (5), p.110312-110312, Article 110312
• Main Authors: Sun, Jian, Yoon, Jaeho, Lee, Moonsup, Lee, Hyun-Kyung, Hwang, Yoo-Seok, Daar, Ira O.
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - physiology; DNA-Binding Proteins - metabolism; eye differentiation; Gene Expression Regulation, Developmental - physiology; Gli3; Hedgehog Proteins - metabolism; Hedgehog signaling; Kruppel-Like Transcription Factors - metabolism; Nerve Tissue Proteins - metabolism; Repressor Proteins - metabolism; Retina - growth & development; rod photoreceptor; RPE; Signal Transduction - physiology; Trans-Activators - metabolism; Transcription Factors - metabolism; Xenopus; Xenopus Proteins - metabolism; Zic5; Zinc Finger Protein Gli3 - metabolism
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •Zic5 regulates differentiation of RPE and rod photoreceptor layer through Hh pathway•Zic5 is co-expressed with Gli3 in developing Xenopus eyes•Gli3 functions as a repressor for Hh signaling in Xenopus eye development•Zic5 binds and stabilizes Gli3 Sun et al. reveal a critical role for Zic5 in regulating the differentiation of retinal pigmented epithelium (RPE) and rod photoreceptor layer by interacting and stabilizing Gli3, which functions predominantly as a repressor for the Hedgehog (Hh) signaling pathway during Xenopus development.