Caramello, Alessia; (2019) Region-specific roles of SOX9 in forebrain oligodendrogenesis and development of the dentate gyrus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

During central nervous system (CNS) development, expression of the SOXE transcription factor SOX9 is up-regulated in neuroepithelial progenitors (NEPs) by E11.5 in the mouse and it is required for their induction and maintenance, as well as for their switch from neurogenesis to gliogenesis. To better characterize its role, Sox9 was conditionally deleted earlier and specifically in the CNS using Sox1Cre, which is active before the onset of Sox9 expression. Oligodendrocyte precursors are initially missing in Sox9fl/fl;Sox1Cre/+ embryos, but recover perinatally. This is due to functional compensation by SOX8, a SOXE member closely related to SOX9, because Sox9fl/fl; Sox1Cre/+;Sox8-/- embryos do not recover oligodendrocytes. Therefore, SOX8 may allow late embryonic oligodendrogenesis in absence of SOX9, by a yet unknown mechanism. The origin of the recovered oligodendrocytes in Sox9fl/fl;Sox1Cre/+ embryos is currently being investigated with in utero electroporation. Sox9fl/fl;Sox1Cre/+ embryos also show defective development of the archicortex, the embryonic structure giving rise to the dentate gyrus (DG). Generation of mature granule neurons and their progenitors is unaffected; however, these fail to reach the developing DG and accumulate close to the ventricle, suggesting a migration defect. In Sox9fl/fl;Sox1Cre/+ mutants, we observed a dramatic reduction of the radial glial scaffold and its astrocytic progenitors, which originate from the adjacent cortical hem (CH) and support granule neuron progenitors migration during DG development. Consequently, in adult Sox9fl/fl;Sox1Cre/+ mice, DG size and neural stem cell numbers are significantly reduced, which may explain their defective memory forming abilities. Therefore, these results suggest that SOX9 is required in the archicortex for formation of the radial glial scaffold, and consequently for the migration of DG granule neurons and their progenitors. This hypothesis is further confirmed by analysis of Sox9fl/fl;NestinCre embryos, where radial glial scaffold and consequently granule neuron progenitor migration, are less affected compared to Sox9fl/fl;Sox1Cre/+. Because Nestin-Cre is acting later in the archicortex compared to Sox1Cre, this highlights an early critical requirement of SOX9 for induction of astrocyte progenitors in the archicortex and, subsequently, DG development. CH-specific deletion of Sox9 is currently being performed to assess this hypothesis. In conclusion, analysis of Sox9 deletion during forebrain development highlights unique temporal- and region-specific functions of this transcription factors for specification of glial cells.

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