Xenopus Sox3 activates sox2 and geminin and indirectly represses Xvent2 expression to induce neural progenitor formation at the expense of non-neural ectodermal derivatives

Abstract

The SRY-related, HMG box SoxB1 transcription factors are highly homologous, evolutionarily conserved proteins that are expressed in neuroepithelial cells throughout neural development. SoxB1 genes are down-regulated as cells exit the cell-cycle to differentiate and are considered functionally redundant in maintaining neural precursor populations. However, little is known about Sox3 function and its mode of action during primary neurogenesis. Using gain and loss-of-function studies, we analyzed Sox3 function in detail in Xenopus early neural development and compared it to that of Sox2. Through these studies we identified the first targets of a SoxB1 protein during primary neurogenesis. Sox3 functions as an activator to induce expression of the early neural genes, sox2 and geminin in the absence of protein synthesis and to indirectly inhibit the Bmp target Xvent2. As a result, Sox3 increases cell proliferation, delays neurogenesis and inhibits epidermal and neural crest formation to expand the neural plate. Our studies indicate that Sox3 and 2 have many similar functions in this process including the ability to activate expression of geminin in naïve ectodermal explants. However, there are some differences; Sox3 activates the expression of sox2, while Sox2 does not activate expression of sox3 and sox3 is uniquely expressed throughout the ectoderm prior to neural induction suggesting a role in neural competence. With morpholino-mediated knockdown of Sox3, we demonstrate that it is required for induction of neural tissue by BMP inhibition. Together these data indicate that Sox3 has multiple roles in early neural development including as a factor required for noggin-mediated neural induction.

Geminin Is Required for Epithelial to Mesenchymal Transition at Gastrulation

“…The striking lack of Geminin in the epidermal ectoderm suggests that Geminin may function in the ectoderm like other preneural genes, such as Sox3 and Zic2 that are required for the induction of neural tissue by BMP inhibition, thereby positioning the neural-epidermal ectodermal border [54,73], consistent with observations that overexpression increases and reductions in Geminin reduce the size of the neural plate in Xenopus [7], Zebrafish [49], and Drosophila [10] embryos. Geminin may then maintain proliferation in the neural ectoderm and prevent premature expression of genes involved in faterestriction [34,35,74].…”

“…Geminin has been suggested to mark the acquisition by the ectoderm of neural competence [73]. The striking lack of Geminin in the epidermal ectoderm suggests that Geminin may function in the ectoderm like other preneural genes, such as Sox3 and Zic2 that are required for the induction of neural tissue by BMP inhibition, thereby positioning the neural-epidermal ectodermal border [54,73], consistent with observations that overexpression increases and reductions in Geminin reduce the size of the neural plate in Xenopus [7], Zebrafish [49], and Drosophila [10] embryos.…”

Establishing neural crest identity: a gene regulatory recipe

“…and epidermal markers, suggesting that neural factors can also repress neural plate border specifiers (Wakamatsu et al, 2004;Rogers et al, 2009). Thus, the cis-regulatory interactions between neural genes and neural plate border specifiers result in a sharp boundary that will separate neural crest from central nervous system progenitors ( Fig.…”

Differential distribution of competence for panplacodal and neural crest induction to non-neural and neural ectoderm

“…Moreover, although expression of Dlx and GATA genes initially requires BMP, they become BMP independent during gastrulation (Kwon et al, 2010), which could underlie the gradual stabilization of non-neural competence that our model predicts. Although it is currently not clear which transcription factors confer neural competence, the early onset of Sox3 expression in the ectoderm, its gradual restriction to neural ectoderm in a complementary pattern to Dlx3 and its ability to repress non-neural markers (including Dlx3 and GATA2) (Penzel et al, 1997;Rogers et al, 2008;Rogers et al, 2009) (G.S., unpublished) make it, at present, a most promising candidate.…”