Alessia Caramello, Francis Crick Institute - London

Friday, April 19th - h 2:00 p.m.
Seminars Room, NICO
Neuroscience Institute Cavalieri Ottolenghi
Regione Gonzole 10, Orbassano (TO)

Alessia Caramello
Francis Crick Institute, London

Early SOX9 expression in the archicortex is required for gliogenesis, granule neuron progenitor migration and dentate gyrus development

Dentate granule neuron progenitors originate in the dentate neuroepithelium (DNE) of the archicortex, from where they migrate to the presumptive dentate gyrus (DG). Their migration is controlled by molecular cues and also relies on a dentate glial scaffold (DGS), arising from progenitors in the adjacent cortical hem (CH).

During central nervous system (CNS) development, conditional deletion of Sox9 using NestinCre impairs neuroepithelial progenitor proliferation and switch from neurogenesis to gliogenesis. Here, we deleted Sox9using Sox1Cre which, contrary to NestinCre, is active exclusively in the CNS, before onset ofSox9 expression.

In adult Sox9^fl/fl; Sox1^Cre/+ mice, DG size and adult neural stem cells proliferation are significantly reduced, while in Sox9^fl/fl; Nestin^Cre/+ mice they are only mildly affected. To explore the origin of this phenotype, we analysed DG development comparing both models.

In Sox9^fl/fl; Sox1^Cre/+ pups, granule neuron progenitor generation is unaffected, however these cells fail to reach the presumptive DG and accumulate close to the DNE, where they ectopically expressmature granule neuron markers.Moreover, the GFAP+ DGSand its ALDH1L1+ gliogenic progenitors arising from the CH are dramatically reduced compared to controls, while other migration cues are not significantly affected. Thissuggests that impaired DG progenitormigration and adult DG phenotype might result from defective DGS formation. Moreover, consistent with the reduced severity of the adult phenotype, both granule neuron migration and DGS are less affected in Sox9^fl/fl; Nestin^Cre/+embryos. We propose this is likely because NestinCreinduces Sox9 deletion 24 hours later thanSox1Crein the archicortex.

In conclusion, early Sox9 expression in the archicortex is necessary for induction of CH gliogenesis and proper DG development. We are further analysing granule neuron progenitor migration using in utero electroporation, identifying SOX9 targets in this context using RNAseq and investigating the role of the DGS in granule neuron migration by performing CH-specific Sox9 deletion.

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