Project ID CM-HD2023_47


Co Supervisor 1A Centre for Developmental Neurobiology / Institute of Psychiatry, Psychology and NeuroscienceWebsite

Co Supervisor 1B Department of Medical and Molecular Genetics/School of Basic and Medical BiosciencesWebsite

Regulation of neural stem cell quiescence by ribosomal activity

Project Description:
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 uncoupling between the transcriptome (mRNA expression) and proteome (protein expression) in quiescence (Rossi et al., bioRxiv). Here, we further exploit our expertise in NSCs[1], RNA biology and genome-scale technologies [2] (Rogriguez-Algarra et al., Genome Biol) 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.

1. To determine which transcripts are being actively translated in quiescent versus active NSCs (mouse hippocampal NSC cultures, polysome fractionation, RNA-seq, bioinformatics)
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).
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).

One representative publication from each co-supervisor:

• Sousa-Nunes R, Yee LL, Gould AP (2011) Fat cells reactivate quiescent neuroblasts via TOR and glial Insulin relays in Drosophila. Nature 471(7339):508-12.

• Holland ML, Lowe R, Caton PW, Gemma C, Carbajosa G, Danson AF, Carpenter AAM, Loche E, Ozanne SE, Rakyan VK (2016) Early life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice. Science 353(6298):495-8.