SoxB1 transcription factors restrict organizer gene expression by repressing multiple events downstream of Wnt signalling

Abstract

SUMMARYFormation of the organizer is one of the most central patterning events in vertebrate development. Organizer-derived signals are responsible for establishing the CNS and patterning the dorsal ventral axis. The mechanisms promoting organizer formation are known to involve cooperation between Nodal and Wnt signalling. However, the organizer forms in a very restricted region, suggesting the presence of mechanisms that repress its formation. Here, we show in zebrafish that the transcription factor Sox3 represses multiple steps in the signalling events that lead to organizer formation. Although -catenin, Bozozok and Squint are known to play major roles in establishing the dorsal organizer in vertebrate embryos, overexpression of any of these is insufficient to induce robust expression of markers of the organizer in ectopic positions in the animal pole, where Sox3 is strongly expressed. We show that a dominant-negative nuclear localisation mutant of Sox3 can cause ectopic expression of organizer genes via a mechanism that activates all of these earlier factors, resulting in later axis duplication including major bifurcations of the CNS. We also find that the related SoxB1 factor, Sox19b, can act redundantly with Sox3 in these effects. It therefore seems that the broad expression of these SoxB1 genes throughout the early epiblast and their subsequent restriction to the ectoderm is a primary regulator of when and where the organizer forms.

Sox2 acts as a transcriptional repressor in neural stem cells

“…Our results were over a short time scale so we do not feel that there was likely to be sufficient time for this to occur but it remains formally possible. This is supported by our earlier observations that the repressive effects of the very similar protein, Sox3, were mimicked by an HMG-engrailed repressor fusion protein [22]. …”

Sox2 Acts in a Dose-Dependent Fashion to Regulate Proliferation of Cortical Progenitors

“…However, of these, only Ccnd1, which encodes for the G1/S phase transition licensing factor Cyclin D1, retained its full ability to promote proliferation when coelectroporated with Sox2 ( Figures 3J-3O). In situ hybridization of electroporated E13.5 cortices or chick neural tubes confirmed that the expression level of Ccnd1 was downregulated by Sox2 and upregulated by shRNA-SoxB1 or a dominant-negative variant of Sox3 (Shih et al, 2010) (dnSoxB1; Figures S4B-S4E). In addition, our single-cell analysis also confirmed a strong negative correlation between the expression levels of Sox2 and Ccnd1 (correlation coefficient À0.132) in cortical NPCs under nonoverexpressing physiological conditions ( Figure 3P).…”

Sox3 Functions in a Cell-Autonomous Manner to Regulate Spermatogonial Differentiation in Mice

“…Second, redundant signaling pathways could function to activate downstream targets of Sox3 and can therefore bypass Sox3. For example, Sox3 has been described as directly controlling Wnt signaling, by inhibiting ␤-catenin expression, in developing zebrafish embryos (50). Third, the progenitor population in young animals and adults may be different and/or contain unique differentiation pathways.…”