The Rb/E2F axis is a key regulator of the molecular signatures instructing the quiescent and activated adult neural stem cell state

Bensun C Fong; Imane Chakroun; Mohamed Ariff Iqbal; Smitha Paul; Joseph Bastasic; Daniel O'Neil; Edward Yakubovich; Anthony T Bejjani; Nastaran Ahmadi; Anthony Carter; Alysen Clark; Gustavo Leone; David S Park; Noël Ghanem; Renaud Vandenbosch; Ruth S Slack

doi:10.1016/j.celrep.2022.111578

The Rb/E2F axis is a key regulator of the molecular signatures instructing the quiescent and activated adult neural stem cell state

Cell Rep. 2022 Nov 1;41(5):111578. doi: 10.1016/j.celrep.2022.111578.

Authors

Bensun C Fong¹, Imane Chakroun¹, Mohamed Ariff Iqbal¹, Smitha Paul¹, Joseph Bastasic¹, Daniel O'Neil¹, Edward Yakubovich¹, Anthony T Bejjani², Nastaran Ahmadi¹, Anthony Carter¹, Alysen Clark¹, Gustavo Leone³, David S Park⁴, Noël Ghanem², Renaud Vandenbosch⁵, Ruth S Slack⁶

Affiliations

¹ University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
² Department of Biology, American University of Beirut, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon.
³ MCW Cancer Centre, Medical College of Wisconsin, Milwaukee, WI, USA.
⁴ Department of Clinical Neurosciences, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Cell Biology, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Anatomy, University of Calgary Calgary AB T2N 4N1 Canada.
⁵ Laboratory of Developmental Neurobiology, GIGA Stem Cells & GIGA Neurosciences, University of Liège, Liège, Belgium; Division of Histology, Department of Biomedical and Preclinical Sciences, University of Liège, Liège, Belgium. Electronic address: [email protected].
⁶ University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada. Electronic address: [email protected].

PMID: 36323247
DOI: 10.1016/j.celrep.2022.111578

Abstract

Long-term maintenance of the adult neurogenic niche depends on proper regulation of entry and exit from quiescence. Neural stem cell (NSC) transition from quiescence to activation is a complex process requiring precise cell-cycle control coordinated with transcriptional and morphological changes. How NSC fate transitions in coordination with the cell-cycle machinery remains poorly understood. Here we show that the Rb/E2F axis functions by linking the cell-cycle machinery to pivotal regulators of NSC fate. Deletion of Rb family proteins results in activation of NSCs, inducing a transcriptomic transition toward activation. Deletion of their target activator E2Fs1/3 results in intractable quiescence and cessation of neurogenesis. We show that the Rb/E2F axis mediates these fate transitions through regulation of factors essential for NSC function, including REST and ASCL1. Thus, the Rb/E2F axis is an important regulator of NSC fate, coordinating cell-cycle control with NSC activation and quiescence fate transitions.

Keywords: CP: Neuroscience; CP: Stem cell research; Rb/E2F pathway; activation; adult neurogenesis; cell fate; molecular signature; neural precursors; neural stem cells; quiescence; stem cell maintenance; transcriptional regulation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult Stem Cells* / metabolism
Cell Cycle
Cell Division
Neural Stem Cells* / metabolism
Neurogenesis / physiology
Retinoblastoma Protein / genetics
Retinoblastoma Protein / metabolism

Substances

Retinoblastoma Protein

Grants and funding

CIHR/Canada