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More than a decade has passed since Zic family zinc finger proteins were discovered to be transcription factors controlling neuroectodermal differentiation (neural induction) in Xenopus laevis embryos. Although BMP-signal blocking has been shown to be a major upregulator of Zic genes in neuroectodermal differentiation, recent studies have revealed that FGF signaling and intracellular calcium elevation are also involved in regulating the expression of Zic genes. Different regulatory mechanisms have been found for the Zic1 and Zic3 genes, raising the possibility that functional synergism between them partly accounts for the integration of BMP-signal blocking and FGF signaling in neuroectodermal differentiation. Furthermore, mammalian Zic1 and Zic3 have been found to be neural-cell-fate-inducing and pluripotency-maintaining factors, respectively, leading us to the intriguing question of whether the mechanism underlying amphibian neuroectodermal differentiation is applicable to mammals. Comprehensive understanding of the Zic family genes is therefore essential for the study of the neuroectodermal differentiation and stem cell biology.
Fig. 1. Gastrulation and NED in Xenopus embryos. Dorsal views of Xenopus embryos at late blastula stage (St. 9), early gastrula stage (St. 10.5), late gastrula (St. 12), and neurula (St. 14). The position of NE, blastopore, Spemannâs organizer, BCNE, and Nieuwkoop center are shown in the right hemisections of the late blastula and early gastrula stage embryos. The dorsal views and staging are based on [59], and the hemisection diagrams are based on [3]
Fig. 2. BMP signaling and its blocking. In the course of gastrulation, natural BMP-signal blocking occurs in BCNE through the physical interaction between BMP2/BMP4 and noggin/chordin. Three ways of experimentally blocking BMP signal in Xenopus embryos are shown: (1) dominant-negative type BMP receptor; (2) Smad6 (inhibitory Smad); and (3) Smad5-sbn (somitabun), which is thought to be deficient in binding to Smad4 and to form an inactive heteromeric complex with intact Smad5 and Smad1, resulting in efficient inhibition of the BMP signaling pathway. Phosphorylation of Smad1 by FGF/MAPK signaling (P on black background) occurs at a different amino acid position from that of BMP receptor-mediated phosphorylation (P on white background), and inhibits the transcriptional activity of Smad1. Natural inhibitory factors for BMP signaling are highlighted with gray
Fig. 3. NED signaling pathways and Zic1/3 genes. BMP-signal blocking, FGF, and calcium signaling regulate the expression of the NED-enhancing transcription factors Zic1 and Zic3
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