Spatial and temporal regulation of cerebral cortex development by the transcription factor pax6

Lamina formation in the developing cortex requires precise generation, migration and differentiation of cortical neurons. Cortical projection neurons originate from progenitors of the embryonic dorsal telencephalon. The transcription factor Pax6 is expressed in apical progenitors (APs) throughout corticogenesis in a rostro-lateralhigh to caudo-mediallow gradient. The current studies focus on elucidating the spatial and temporal role of Pax6 in cortical development. I first analysed the cortex of PAX77 transgenic mice that overexpress Pax6 in its normal domains of expression. I show that Pax6 overexpression acts cell-autonomously to reduce the proliferation of late cortical progenitors specifically, resulting in the formation of thinner superficial layers in the PAX77 cortex. Increased levels of Pax6 lengthen the cell cycle of APs and drive the system towards neurogenesis. These effects are specific to late stages of corticogenesis, when superficial layer neurons are normally generated, in cortical regions that express Pax6 at the highest levels. The number of superficial layer neurons is reduced in postnatal PAX77 mice, while radial migration and lamina specification of cortical neurons are not affected by Pax6 overexpression. Then, Pax6 was conditionally inactivated in cortical progenitors at mid- or late-stages of corticogenesis by using a tamoxifen-inducible Emx1-CreER line. I report a novel requirement of Pax6 for continuous suppression of ventral fates and concurrent maintenance of an appropriate dorsal identity in cortical progenitors. Pax6 ablation at either mid- or late-stages of corticogenesis increases the proliferation of late cortical progenitors at all levels across the rostral-caudal axis. In the absence of Pax6 from mid-corticogenesis, late-born neurons are severely under-represented and misspecified in superficial layers of the mutant cortex. Notably, Pax6 inactivation during late corticogenesis also affects superficial laminar fate; although the numbers of late-born cortical neurons are not severely affected in superficial layers of the mutant cortex, substantial numbers of late-born cells fail to migrate to appropriate laminar positions and accumulate in the ventricular zone (VZ) of the postnatal mutant cortex. Collectively, these gain- and loss-of-function studies suggest that disruption of Pax6 levels during different developmental time points leads ultimately to impaired formation of superficial cortical layers but through different cellular and molecular mechanisms.EThOS - Electronic Theses Online ServiceGBUnited Kingdo