Neural stem cells (NSCs) are self-renewing multipotent progenitors that generate various cell types in the central nervous system (CNS). It is crucial to understand how NSCs regulate proliferation as this controls development, maintenance, and repair of the CNS, as well as learning, memory and mood.
Stem cells pause divisions by entering a state called quiescence, reversible cell-cycle arrest accompanied by diminished biosynthetic activity. Quiescence protects cells against environmental insults, replicative exhaustion, and proliferation-induced mutations. Cancer stem cells also undergo quiescence, which renders them refractory to therapies. Mechanisms governing quiescence are therefore of great biological and clinical interest but only partially understood.
We recently found that quiescent NSCs display nuclear biasing of many mRNAs relative to active NSCs, as well as smaller-scale cytoplasmic biasing of others. Nuclear or cytoplasmic biasing of mRNA was associated with decreased or increased protein synthesis (>80% cases), as determined by proteomics, leading to uncoupling between the transcriptome and proteome in quiescence (Fig. 1).
Here, we further exploit our expertise in NSCs, RNA biology and genome-scale technologies to investigate how gene expression is regulated in the transition between quiescent and active NSCs at the level of mRNA nuclear export and translation to understand how this contributes to reversible alterations in stem cell behaviour.
Aim 1: To determine which transcripts are being actively translated in quiescent versus active NSCs (mouse hippocampal NSC cultures, polysome fractionation, RNA-seq, bioinformatics)
Aim 2: To determine if ribosome composition changes in quiescent versus active NSCs (mouse hippocampal NSC cultures, polysome fractionation, RNA-seq, RNA modification profiling, bioinformatics, proteomics).
Aim 3: To validate mechanisms of regulation for the model produced in Aims 1 and 2 (gene perturbations in mouse NSCs and Drosophila in vivo, stainings, microscopy, image analyses).
Regulation of neural stem cell quiescence by ribosomal activity
Representative Publications
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