Making sense of adult neural stem cell heterogeneities

Neural stem cell (NSC) populations ensure the production of neurons and astroglial cells in the vertebrate adult brain. NSC activity persists at long-term in zebrafish, but exhausts rapidly in mouse from the young adult stage. Using long-term genetic clonal tracing and intravital imaging in the zebrafish adult pallium (dorsal telencephalon), we revealed that two distinct NSC sub-populations cooperate to ensure population maintenance and neurogenesis (1, 2). These sub-populations are endowed with self-renewal vs neurogenesis capacity and are organized in a functional hierarchy. Using sc-omics, we and others observed that these sub-population are themselves molecularly heterogeneous (3–6). The biological significance and regulation of these heterogeneities are unknown, as well as how they remain balanced in time and space over a lifetime. I will show our latest results on these questions, showing how we are taking in situ approaches and readouts of Notch3 signaling to decipher individual NSC trajectories and their coordination within the transcriptomic and physical spaces.

References

1.    E. Than-Trong, B. Kiani, N. Dray, S. Ortica, B. Simons, S. Rulands, A. Alunni, L. Bally-Cuif, Lineage hierarchies and stochasticity ensure the long-term maintenance of adult neural stem cells. Sci Adv 6, eaaz5424 (2020).

2.    L. Mancini, B. Guirao, S. Ortica, M. Labusch, F. Cheysson, V. Bonnet, M. S. Phan, S. Herbert, P. Mahou, E. Menant, S. Bedu, J.-Y. Tinevez, C. Baroud, E. Beaurepaire, Y. Bellaiche, L. Bally-Cuif, N. Dray, Apical size and deltaA expression predict adult neural stem cell decisions along lineage progression (2023) p. eadg7519.

3.    D. Morizet, I. Foucher, A. Alunni, L. Bally-Cuif, Reconstruction of macroglia and adult neurogenesis evolution through cross-species single-cell transcriptomic analyses. Nat Commun 15, 3306 (2024).

4.    D. Morizet, I. Foucher, I. Mignerey, A. Alunni, L. Bally-Cuif, Notch signaling blockade links transcriptome heterogeneity in quiescent neural stem cells with reactivation routes and potential. Sci. Adv. 11, eadu3189 (2025).

5.    M. I. Cosacak, P. Bhattarai, S. Reinhardt, A. Petzold, A. Dahl, Y. Zhang, C. Kizil, Single-Cell Transcriptomics Analyses of Neural Stem Cell Heterogeneity and Contextual Plasticity in a Zebrafish Brain Model of Amyloid Toxicity. Cell Rep 27, 1307-1318.e3 (2019).

6.    N. Mitic, A. Neuschulz, B. Spanjaard, J. Schneider, N. Fresmann, K. T. Novoselc, T. Strunk, L. Münster, P. Olivares-Chauvet, J. Ninkovic, J. P. Junker, Dissecting the spatiotemporal diversity of adult neural stem cells. Mol Syst Biol 20, 321–337 (2024).