Zulfiqar Ali Laghari

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

Formation 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 β-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

BackgroundThe transcription factor, Sox2, is central to the behaviour of neural stem cells. It is also one of the key embryonic stem cell factors that, when overexpressed can convert somatic cells into induced pluripotent cells. Although generally studied as a transcriptional activator, recent evidence suggests that it might also repress gene expression.ResultsWe show that in neural stem cells Sox2 represses as many genes as it activates. We found that Sox2 interacts directly with members of the groucho family of corepressors and that repression of several target genes required this interaction. Strikingly, where many of the genes activated by Sox2 encode transcriptional regulators, no such genes were repressed. Finally, we found that a mutant form of Sox2 that was unable to bind groucho was no longer able to inhibit differentiation of neural stem cells to the same extent as the wild type protein.ConclusionsThese data reveal a major new mechanism of action for this key transcription factor. In the context of our understanding of endogenous stem cells, this highlights the need to determine how such a central regulator can distinguish which genes to activate and which to repress.