Fig. 1.

Important proliferation factors that mediate the early transcriptional response of BMP inhibition and FGF signaling downstream of neural induction. After neural tissue is induced through active FGF and Ca²⁺ signaling and BMP inhibition, Zic1, Zic3 and Foxd4l1 are up-regulated [29, 34–36, 48, 49]. Foxd4l1 and Zic3 are downstream targets of FGF signaling, possibly mediated by AP-1 [32–34, 263, 264], whereas Zic1 is an immediate early gene of BMP inhibition and is driven by a BMP inhibitor-responsive promoter module (BIRM) [34, 35]. Geminin (Gem) and Zic2 are regulated by Foxd4l1 and promote Notch signaling and inhibition of proneural gene Neurogenin [31, 52–55]. Zic1 also promotes Notch signaling and directly represses proneural gene Math1 [40, 41]. Cross-regulation between Geminin, Zic, SoxB1 (Sox2 and Sox3), Sox11, and Notch maintains proliferation in the neuroectoderm [39, 50, 54–56]. Potential inhibitory interactions between Sox11 and Zic genes are explored in Moody 2013, but not displayed here. Collectively, proneural genes Neurogenin and Math1 are repressed by these proliferative signals, and primary neurogenesis is inhibited as a result. RA inhibits neural proliferation quite early in this process by downregulating the expression of Geminin, Zic1/2/3, and Notch [22]