Pax6 Levels in Neural Stem Cell Self-Renewal Figure 8. A neurogenesis and self-renewal regulatory circuit operating in neocortical stem cells, regulated by Pax6. (A) Pax6 binding and regulation data indicate that Pax6 levels are critical in maintaining the balance between stem cell maintenance, neurogenesis and SVZ genesis, as well as enforcing cortical identity. Combining these data with published data on genes downstream of Neurog2, Ascl1 and Hes1 (see text for details) enables construction of a basic network regulating cortical stem cell neurogenesis. Under normal conditions, Pax6 positively regulates Neurog2 and negatively regulates Ascl1 (Mash1), while directly and indirectly repressing the transcription factors Isl1 and Lhx8 respectively, both required for inhibitory interneuron genesis. Overall, this promotes genesis of glutamatergic projection neurons. Pax6 also positively regulates basal progenitor cell genes, including Eomes/Tbr2. Thick lines indicate direct regulation, thin lines indicate evidence from expression studies. (B) Loss of Pax6 function (Sey/Sey) removes the positive regulation of Neurog2 and the negative regulation of Ascl1, Lhx8 and Isl1. This would be predicted to result in the production of GABAergic interneurons in the cortex, as has been previously observed [52]. The loss of Pax6 also removes the positive regulation of the set of basal progenitor cell genes, however this is compensated for many of those genes in large part by the upregulation of Ascl1, with the exception of Eomes/Tbr2. Thus an SVZ is still generated in the absence of Pax6, but without Pax6 it loses its cortical identity and becomes Ascl1- expressing, similar to the SVZ of the ventral forebrain [14]. (C) Increasing the levels of Pax6 (indicated by thick lines) would be predicted to result in an over-production of basal progenitor cells by increasing Neurog2 expression and synergising with Neurog2 to increase expression of basal progenitor cell determinants, including Eomes/Tbr2. This increase in neurogenesis would potentially be at the expense of stem cell maintenance, although both Neurog2 and Pax6 increase expression of the stem cell maintenance factor Hes5. doi:10.1371/journal.pgen.1000511.g008 PLoS Genetics | www.plosgenetics.org 11 June 2009 | Volume 5 | Issue 6 | e1000511