Role of the transcription factors COUP-TFI and Pax6 in neural stem cell self-renewal and neurogenesis during mouse cortical development

Area-specific cytoarchitecture implies a tight spatiotemporal control on the lateral expansion of individual cortical areas coupled to radial growth, which will determine cortical thickness and cell-type specification. The mode of neural-progenitor cell divisions determines cell number and direction of cortical expansion and growth. While progenitors initially divide symmetrically to increase the stem cell pool, asymmetrically dividing radial glial cells will subsequently expand the pool of differentiating cells. The molecular mechanisms that regulate the switch from symmetric to asymmetric division during cortical arealization are poorly understood. The transcription factors COUP-TFI and Pax6 are expressed in opposite gradients and required to co-ordinately control areal and laminar identity during corticogenesis. Recently, Pax6 has been demonstrated to regulate the orientation and mode of cell divisions in the mouse cortex. In the first part of my work, I found that in the absence of COUP-TFI function cortical cells abnormally proliferate over time, implying that COUP-TFI is responsible for maintaining a proper progenitor pool during development. Next, by generating double compound mutants between COUP-TFI and Pax6, I found that lowering the gene dosage of Pax6 in COUP-TFI mutants, and vice versa, of COUP-TFI in Pax6 mutants, rescued the reciprocal mutant phenotype. In vivo analysis on cortical primordia using markers of apical (self-renewal) versus basal (neurogenic) progenitors, confirmed most of the in vitro results, even if the in vivo situation resulted to be more complex. Overall, these data strongly suggest a molecular cross-regulation between COUP-TFI and Pax6 during the maintenance of a proper balance between the stem/ progenitor and committed precursor pools, most probably acting on similar target genes