Retinoic acid signaling and neuronal differentiation

Abstract

The identification of neurological symptoms caused by vitamin A deficiency pointed to a critical, early developmental role of vitamin A and its metabolite, retinoic acid (RA). The ability of RA to induce post-mitotic, neural phenotypes in various stem cells, in vitro, served as early evidence that RA is involved in the switch between proliferation and differentiation. In vivo studies have expanded this "opposing signal" model, and the number of primary neurons an embryo develops is now known to depend critically on the levels and spatial distribution of RA. The proneural and neurogenic transcription factors that control the exit of neural progenitors from the cell cycle and allow primary neurons to develop are partly elucidated, but the downstream effectors of RA receptor (RAR) signaling (many of which are putative cell cycle regulators) remain largely unidentified. The molecular mechanisms underlying RA-induced primary neurogenesis in anamniote embryos are starting to be revealed; however, these data have been not been extended to amniote embryos. There is growing evidence that bona fide RARs are found in some mollusks and other invertebrates, but little is known about their necessity or functions in neurogenesis. One normal function of RA is to regulate the cell cycle to halt proliferation, and loss of RA signaling is associated with dedifferentiation and the development of cancer. Identifying the genes and pathways that mediate cell cycle exit downstream of RA will be critical for our understanding of how to target tumor differentiation. Overall, elucidating the molecular details of RAR-regulated neurogenesis will be decisive for developing and understanding neural proliferation-differentiation switches throughout development.

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 [, –36, 48, 49]. Foxd4l1 and Zic3 are downstream targets of FGF signaling, possibly mediated by AP-1 [–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 [, –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 [, , –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]

Fig. 2

MAFFT alignment of RARα2 in Homo sapiens versus Lophotrochozoan species. Alignment begins with the conserved DNA-binding domain of RARα2 (no conservation is observed in the N-terminal region)