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Dynamics and Homeostasis of Germinal Zones in the Adult Vertebrate Brain

Final Report Summary - SYSTEMATICS (Dynamics and Homeostasis of Germinal Zones in the Adult Vertebrate Brain)

The SyStematics project aimed to provide a comprehensive, multi-scale view of the molecular and cellular rules driving neural stem cell (NSC) pools homeostasis in the vertebrate brain. It relied on a unique experimental system, the zebrafish adult pallium (dorsal telencephalon). This model was brought by the team at the forefront of adult NSC research for its enrichment in NSCs and its amenability to intravital imaging analyses, bridging the single cell and population scales for the first time in vivo in an intact vertebrate. Towards this goal, the SyStematics projects focused on a key parameter of adult NSC pools homeostasis, namely the maintenance of a tight balance between NSC quiescence and activation.
At the individual cell level, we used RNA profiling under various physiological, mutant and experimentally manipulated conditions in vivo, to gain insight into the molecular control of NSC quiescence. We could identify and dissect two NSC quiescence-promoting pathways: Notch3 signalling and microRNA-9. We demonstrated in particular that Notch3 signalling promotes NSC quiescence and stemness via different molecular targets, and that miR-9 acts in this process via an unconventional, nuclear mechanism. At the population level, we combined genetic lineage analyses, live imaging and statistical biophysical modelling to study NSC lineage dynamics, and could generate the first integrated model describing population behavior over time. We identified and tracked the embryonic origin of adult NSCs, and, in adults, showed that the long-term maintenance of NSC pools relies on their hierarchical organization into sub-functionalized pools that ensure amplification, self-renewal and neurogenesis. In particular, we could provide evidence for the existence of an as yet unsuspected “source” population generating novel NSCs during adulthood and contributing to the long-term maintenance of the overall pool. Using scRNAseq, we confirmed the existence of several molecularly distinct groups of NSCs differing in their state/lineage position, and enerated a rich molecular dataset for future functional investigations. Finally, we brought population analyses to a spatio-temporal dimension, by developing an intravital imaging method permitting to track adult NSCs in their endogenous niche over weeks to months through the skin and skull of live adults. With this, we could address how NSC recruitment events are patterned within adult brain germinal zones. We revealed a previously unsuspected level of control that permits the geometries of germinal pools, and the positioning of NSC recruitment events, to be homogeneously propagated over time, based on cell-cell interactions operating between NSCs at different space ranges and with temporal delays.
Together, this work provides a comprehensive understanding of how heterogeneities in NSC states and fates are generated, maintained, modulated and propagated in time and space to account for the global long-term dynamic of NSC pools in the adult vertebrate brain.