Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy.
Krieger, Teresa G
Muraro, Mauro J
Stange, Daniel E
Rivron, Nicolas C
van de Wetering, Marc
van Es, Johan H
van Oudenaarden, Alexander
Proceedings of the National Academy of Sciences
National Academy of Sciences
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Basak, O., Krieger, T. G., Muraro, M. J., Wiebrands, K., Stange, D. E., Frias-Aldeguer, J., Rivron, N. C., et al. (2018). Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy.. Proceedings of the National Academy of Sciences, 115 (4), E610-E619. https://doi.org/10.1073/pnas.1715911114
The adult mouse subependymal zone provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential, and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem-cell number before some return to quiescence. This behavior is best explained by stochastic fate decisions, where stem-cell number within a shared niche fluctuates over time. Fate mapping proliferating cells using a Ki67iresCreER allele confirms that active NSCs reversibly return to quiescence, achieving long-term self-renewal. Our findings suggest a niche-based mechanism for the regulation of NSC fate and number.
cellular dynamics, ki67, modeling, neural stem cells, single-cell sequencing
This work was supported by NIRM/ Clevers and Stichting Vrienden van het Hubrecht (O.B.), EU/232814-StemCellMark and Skolkovo 077 MPA (J.H.v.E.), NIH/MIT Subaward 5710002735 (to D.E.S.), KWF/PF-HUBR 2007-3956 and Stichting Vrienden van het Hubrecht (M.v.d.W.), European Research Council Advanced Grant ERC-AdG 294325-GeneNoiseControl (to K.W. and A.v.O.), and Wellcome Trust Grant 098357/Z/12/Z (to B.D.S.).
Wellcome Trust (098357/Z/12/Z)
External DOI: https://doi.org/10.1073/pnas.1715911114
This record's URL: https://www.repository.cam.ac.uk/handle/1810/275901