REGULATION OF EMBRYONIC AND ADULT NEURAL STEM CELLS DURING MOUSE CORTICOGENESIS

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 influences 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 divisions during cortical arealization are poorly understood. We found that the transcriptional regulator COUP-TFI, described by us to be a crucial areal patterning gene during development, restricts the stem cell pool during corticogenesis. In its absence the number of cortical stem cells/progenitors dramatically increases and progenitors become capable of long-term expansion in vitro. We also show that COUP-TFI directly regulates Pax6 expression during symmetric and asymmetric progenitor divisions, and during the transition between neurogenesis and gliogenesis. Thus, our data suggest that the transcription factors COUP-TFI and Pax6, normally expressed in opposite gradients and required to co-ordinately control areal and laminar identity during development, co-regulate each other during critical periods of cortical expansion. Our work also shows that COUP-TFI is maintained in neural stem cells in the two major neurogenic regions of the adult brain, the subventricular zone of the lateral ventricle (SVZ) and the subgranular zone (SGZ) of the hippocampus. To challenge its role in adult neural stem cells, we have genetically inactivated COUPTFI in cortical progenitors, in cortical post-mitotic neurons and at post-natal stages. When COUP-TFI is inactivated in all cortical progenitors from E10.5, the dentate gyrus is reduced and displaced and the lateral ventricle is hugely enlarged in adult mice. In mouse brains in which COUP-TFI is inactivated solely in post-mitotic neurons, no alterations are detected in the hippocampus, indicating a key role for COUP-TFI in dentate gyrus granule maturation during early stages of development. Finally, absence of COUP-TFI at P3 shows an increase of the number of stem cells in the dentate gyrus, in agreement with our embryonic analysis. In summary, our results indicate that COUP-TFI is implicated in regulating particular aspects of stem cell development, and propose COUP-TFI as a novel factor required in modulating the rate of embryonic and adult neural stem cells.