Effetto della delezione di SOX2 sull'attivazione neurogenica degli astrociti striatali indotta da lesione.

The adult brain retains the capacity to produce new neurons in two specialized niches where a sub-population of astrocytes acts as neural stem cells. Recent studies have proven that after excitotoxic lesion or stroke in mice, striatal astrocytes can activate a latent neurogenic potential also outside the canonical neurogenic niches. However, the cellular and molecular mechanisms regulating the transition of parenchymal astrocytes and their environment towards neurogenesis remain unclear. After QA lesion, neurogenic activation occurs about 10 days after the initial phase of reactivity when striatal astrocytes sporadically activate throughout the striatum generating clusters of intermediate progenitors that transiently expand generating neurons. Preliminary studies indicated that the TF Sox2 is strongly upregulated shortly after lesion in striatal astrocytes and its conditional deletion completely abolished the neurogenic response. This TF is involved in the maintenance of stem cells potential in adult and embryonic neural progenitors and experimental modulation of its expression indicate that is sufficient for astrocytes neurogenic activation and it is necessary for astrocytes reactivity. Astrocytes reactivity and neurogenic activation are two astrocytes states that can co-exists in specific conditions, such as after QA lesion. Whether the abrogation of striatal neurogenesis after Sox2 deletion is due to an impairment during the reactivity phase or if Sox2 could be required also at later phases remained to be established. To answer this question, we took advantage of the GLASTCreERT2:Sox2fl/fl mice in which Tamoxifen administration induce Sox2 deletion in about 50% of astrocytes. Tamoxifen was administered after the early reactive astrogliosis but either before or after the neurogenesis onset. Deleting the factor when neurogenesis was ongoing did not reduced the level of neurogenesis in mutant animals and interestingly the fraction of Sox2 negative neurogenic foci did not differ from the fraction of Sox2 negative astrocytes, strongly suggesting an equal probability of neurogenic activation between Sox2 positive and negative astrocytes. By contrast its deletion before neurogenesis onset completely abolished the neurogenic response, indicating that the activation of striatal astrocytes neurogenic potential critically depends on Sox2 in the phase immediately preceding neurogenesis onset. Preliminary results deleting Sox2 with a sparse mutation approach suggests that this impairment is due to a combination of cell autonomous and non-cell autonomous effects. These results suggest that Sox2 expression is necessary to prime a neurogenic competent state in astrocytes before neurogenesis onset at least in part by modulating the striatal environment. Overall, these data support a model where the awakening of striatal astrocytes neurogenic competence and neuronal lineage progression are dissociable components of a complex multi-step process regulated both at cellular and environmental level.