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

TY - JOUR

T1 - Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy

AU - Basak, Onur

AU - Krieger, Teresa G

AU - Muraro, Mauro J

AU - Wiebrands, Kay

AU - Stange, Daniel E

AU - Frias-Aldeguer, Javier

AU - Rivron, Nicolas C

AU - van de Wetering, Marc

AU - van Es, Johan H

AU - van Oudenaarden, Alexander

AU - Simons, Benjamin D

AU - Clevers, Hans

PY - 2018/1/23

Y1 - 2018/1/23

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Lineage

KW - Cell Proliferation

KW - Lateral Ventricles/cytology

KW - Mice

KW - Neural Stem Cells/physiology

KW - Neurogenesis

KW - Receptors, Tumor Necrosis Factor/metabolism

KW - Single-Cell Analysis

KW - Stem Cell Niche

KW - Transcriptome

U2 - 10.1073/pnas.1715911114

DO - 10.1073/pnas.1715911114

M3 - Article

C2 - 29311336

SN - 0027-8424

VL - 115

SP - E610-E619

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 4

ER -