Neural stem cells alter nucleocytoplasmic partitioning and accumulate nuclear polyadenylated transcripts during quiescence

Abstract

Quiescence is a cellular state characterised by reversible cell-cycle arrest and diminished biosynthetic activity that protects against environmental insults, replicative exhaustion and proliferation-induced mutations1. Entry into and exit from this state controls development, maintenance and repair of tissues plus, in the adult central nervous system, generation of new neurons and thus cognition and mood2-4. Cancer stem cells too can undergo quiescence, which confers them resistance to current therapies5,6. Despite clinical relevance, quiescence is poorly understood and is defined functionally given lack of molecular markers. Decrease of the most resource-intensive cellular process of protein synthesis is a feature of quiescence, controlled across species and cell types by inhibition of the Target of Rapamycin pathway1,7. Here, we combine Drosophila genetics and a mammalian model to show that altered nucleocytoplasmic partitioning and nuclear accumulation of polyadenylated RNAs are novel evolutionarily conserved hallmarks of quiescence regulation. These mechanisms provide a previously unappreciated regulatory layer to reducing protein synthesis in quiescent cells, whilst priming them for reactivation in response to appropriate cues.

Could a Different View of Quiescence Help Us Understand How Neurogenesis Is Regulated?

“…Transcriptional profiling is not an accurate readout of the position of NSCs along the quiescence to activation transition. Recent data has pointed out that unlike other cell types, the correlation between mRNA and protein content in quiescent NSCs is very poor ( Rossi et al, 2021 ). In addition, several pieces of evidence point to post-transcriptional and post-translational mechanisms being the main drivers of the transition of adult NSCs between quiescence and activation.…”

Dephosphorylation of 4EBP1/2 Induces Prenatal Neural Stem Cell Quiescence

“…The role of bone morphogenetic protein 4 (BMP4) in directing differentiation and maintenance of stem cells in the V-SVZ and dentate gyrus has been extensively described (Li et al, 1998; Mira et al, 2010). BMP4 has been reported to induce a reversible quiescence in vitro in various stem cell populations within 72 hours, including postnatal neural stem cells (Knobloch et al, 2017; Mira et al, 2010; Rossi et al, 2021), but has not been tested in prenatal NSCs.…”

“…mTOR has been shown to regulate the balance of activation and quiescence in other stem cell populations (Cho & Hwang, 2012; Nieto-Gonzalez et al, 2019; Rodgers et al, 2014). In postnatal NSCs, mTOR also regulates preferential translation of specific mRNA transcripts as stem cells are activated to divide — that is, upon exit from quiescence (Baser et al, 2019; Rossi et al, 2021). The data shown here illuminate a role for this kinase in embryonic NSC quiescence.…”

“…The mechanistic/mammalian target of rapamycin (mTOR) kinase is a principal regulator of cell growth (Laplante & Sabatini, 2012; G. Y. Liu & Sabatini, 2020) that has been shown to regulate the quiescence of other stem cell populations, including in postnatal NSCs (Cho & Hwang, 2012;Nieto-González et al, 2019;Rodgers et al, 2014;Rossi et al, 2021;Sousa-Nunes et al, 2011). However, this potential relationship has not yet been explored in embryonic NSCs.…”