CRISPR–Cas9 screens reveal regulators of ageing in neural stem cells

Tyson J. Ruetz, Angela N. Pogson, Chloe M. Kashiwagi, Stephanie D. Gagnon, Bhek Morton, Eric D. Sun, Jeeyoon Na, Robin W. Yeo, Dena S. Leeman, David W. Morgens, C. Kimberly Tsui, Amy Li, Michael C. Bassik and Anne Brunet ()
Additional contact information
Tyson J. Ruetz: Stanford University
Angela N. Pogson: Stanford University
Chloe M. Kashiwagi: Stanford University
Stephanie D. Gagnon: Stanford University
Bhek Morton: Stanford University
Eric D. Sun: Stanford University
Jeeyoon Na: Stanford University
Robin W. Yeo: Stanford University
Dena S. Leeman: Stanford University
David W. Morgens: Stanford University
C. Kimberly Tsui: Stanford University
Amy Li: Stanford University
Michael C. Bassik: Stanford University
Anne Brunet: Stanford University

Nature, 2024, vol. 634, issue 8036, 1150-1159

Abstract: Abstract Ageing impairs the ability of neural stem cells (NSCs) to transition from quiescence to proliferation in the adult mammalian brain. Functional decline of NSCs results in the decreased production of new neurons and defective regeneration following injury during ageing1–4. Several genetic interventions have been found to ameliorate old brain function5–8, but systematic functional testing of genes in old NSCs—and more generally in old cells—has not been done. Here we develop in vitro and in vivo high-throughput CRISPR–Cas9 screening platforms to systematically uncover gene knockouts that boost NSC activation in old mice. Our genome-wide screens in primary cultures of young and old NSCs uncovered more than 300 gene knockouts that specifically restore the activation of old NSCs. The top gene knockouts are involved in cilium organization and glucose import. We also establish a scalable CRISPR–Cas9 screening platform in vivo, which identified 24 gene knockouts that boost NSC activation and the production of new neurons in old brains. Notably, the knockout of Slc2a4, which encodes the GLUT4 glucose transporter, is a top intervention that improves the function of old NSCs. Glucose uptake increases in NSCs during ageing, and transient glucose starvation restores the ability of old NSCs to activate. Thus, an increase in glucose uptake may contribute to the decline in NSC activation with age. Our work provides scalable platforms to systematically identify genetic interventions that boost the function of old NSCs, including in vivo, with important implications for countering regenerative decline during ageing.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-07972-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:634:y:2024:i:8036:d:10.1038_s41586-024-07972-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-07972-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().