Sox proteins and neurogenesis

The primordium of the central nervous system is specified in a process called neural induction at which point the ectoderm is subdivided into the epidermal ectoderm and the neural plate. With time the neural plate will thicken, fold and form the neural tube. The progenitor cells within the neural tube will later give rise to all neurons and glial cells in the adult central nervous system. Soon after the formation of the neural tube neural progenitor cells stop proliferate and start to express neuronal characters. These events are tightly regulated by a number of different signaling pathways. In this thesis I have studied how SoxB proteins regulate neurogenesis and the maintenance of the neural progenitor pool.

In Paper I we examined the role of Sox21 in regulating neurogenesis. We show that Sox21 promotes neurogenesis, opposite to the activity of the SoxB1 factors (Sox1-3) that has been shown to repress neurogenesis. Sox21 and Sox1-3 bind a similar set of target genes and the effect of Sox21 is mediated through a direct counteraction of Sox1-3 activity. Therefore the intrinsic balance of Sox21 and Sox1-3 activities is important in deciding whether a cell should remain progenitor or commit to differentiation. The proneural proteins Ngn2 and Mash1 have been shown to shift this balance by upregulating Sox21 expression as a way to promote neurogenesis. Since a balanced expression of Sox21 and Sox1-3 is important to maintaining the neural progenitor pool we wanted to find out more about how Sox21 transcription is regulated.

In Paper II we identified a Sox21 enhancer that is active in neural progenitors. Sox1-3 and E proteins synergistically activate this Sox21 enhancer and upregulate Sox21 transcription in vivo. Sox1-3/E protein mediated activation of the Sox21 enhancer is repressed by Sox21, suggesting a cross-regulatory interaction between Sox1-3 and Sox21. Interestingly, the proneural protein Ngn2 is interfering with this Sox1-3/E protein activity, suggesting a novel mechanism where Ngn2 is opposing Sox1-3 activation of neural progenitor gene expression. Both Notch signaling and the Sox1-3 factors are functionally similar in suppressing neurogenesis but it is not clear to whether these signaling pathways are functionally interacting.

In Paper III we have addressed this question. We show that both Notch and Sox1-3 repress proneural function, but they do so at distinct regulatory levels. Notch signaling is repressing transcription of proneural proteins and E proteins whereas Sox1-3 suppresses the proneural proteins function to promote neurogenesis. Overexpression of Sox3 maintain the progenitor pool even in the absence of Notch signaling, whereas Notch signaling requires Sox1-3 activity to maintain neural progenitors in an undifferentiated state.

List of scientific papers

I. Magnus Sandberg, Magdalena Källström and Jonas Muhr (2005). "Sox21 promotes the progression of vertebrate neurogenesis." Nature Neuroscience. 8: 995-1001.
https://pubmed.ncbi.nlm.nih.gov/15995704

II. Magnus Sandberg, Maria Bergsland, Idha Kurtsdotter and Jonas Muhr. (1970). "Identification of Sox21 enhancer elements reveal cross-regulatory interactions between group SoxB proteins." [Manuscript]

III. Johan Holmberg, Emil Hansson, Michal Malewicz, Magnus Sandberg, Thomas Perlmann, Urban Lendahl and Jonas Muhr. (2008). "SoxB1 transcription factors and Notch signaling use distinct mechanisms to regulate proneural gene function and neural progenitor differentiation." Development. 135: 1843-1851.
https://pubmed.ncbi.nlm.nih.gov/18417619