A Nuclear Role for miR-9 and Argonaute Proteins in Balancing Quiescent and Activated Neural Stem Cell States

Summary Throughout life, adult neural stem cells (NSCs) produce new neurons and glia that contribute to crucial brain functions. Quiescence is an essential protective feature of adult NSCs; however, the establishment and maintenance of this state remain poorly understood. We demonstrate that in the adult zebrafish pallium, the brain-enriched miR-9 is expressed exclusively in a subset of quiescent NSCs, highlighting a heterogeneity within these cells, and is necessary to maintain NSC quiescence. Strikingly, miR-9, along with Argonaute proteins (Agos), is localized to the nucleus of quiescent NSCs, and manipulating their nuclear/cytoplasmic ratio impacts quiescence. Mechanistically, miR-9 permits efficient Notch signaling to promote quiescence, and we identify the RISC protein TNRC6 as a mediator of miR-9/Agos nuclear localization in vivo. We propose a conserved non-canonical role for nuclear miR-9/Agos in controlling the balance between NSC quiescence and activation, a key step in maintaining adult germinal pools.
Graphical Abstract
Highlights • miR-9 highlights a state heterogeneity among adult quiescent neural stem cells (NSC) • miR-9 maintains NSC quiescence notably through permitting efficient Notch signaling • miR-9, along with Argonaute proteins, is present in the nucleus of adult quiescent NSCs • Active nucleo-cytoplasmic shuttling of miR-9/Ago impacts NSCs quiescence status
An essential protective feature of adult neural stem cells is their relative quiescence. Katz et al. identify microRNA-9 as crucial factor that maintains adult NSCs quiescence and sets a heterogeneity within these cells, through a non-canonical nuclear mode of action.