Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy

Onur Basak, Teresa G. Krieger, Mauro J. Muraro, Kay Wiebrands, Daniel E. Stange, Javier Frias-Aldeguer, Nicolas C. Rivron, Marc van de Wetering, Johan H. van Es, Alexander van Oudenaarden, Benjamin D. Simons, and Hans Clevers

Published: 07/11/2017


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.

Full Access Link: Proceedings of the National Academy of Sciences of the United States of America