Dual recombinase-mediated intersectional genetics defines the functional heterogeneity of neural stem cells in adult hippocampus

ABSTRACT The Cre-lox site-specific recombinase system is one of the most powerful and versatile technology platforms for studying neural stem cells (NSCs) in adult brain, which is now

challenged due to the complex and dynamic nature of in vivo gene expression. In this study, we develop an inducible dual recombinase-mediated intersectional genetics by combining Dre-rox and

Cre-lox recombination technologies to specifically target two subpopulations of NSCs (α- and β-NSCs). By visiting their cell lineage and functionality, we find that α- and β-NSCs display

distinct self-renewal and differentiation potential, as well as differential responses to external stimuli. Notably, in contrast to α-NSCs, the number of β-NSCs is not affected in aged mice

and an APP/PS1 mouse model of Alzeimer’s disease. Single cell transcriptome analysis reveals divergent molecular signatures between type α- and β-NSCs and identifies PRMT1 as an important

regulatory element to differentially regulate the neurogenic potential of α- and β-NSCs. Inhibition of PRMT1 specifically enhances the neurogenic capacity of β-NSCs and promotes the

cognition functions in aged mice. Importantly, PRMT1 inhibition combined with increased BDNF levels pharmacologically ameliorates the cognitive impairments in APP/PS1 mice. Together, our

study suggests that understanding the functional heterogeneity of NSCs might pave the way for harnessing the specific subpopulation of NSCs to treat brain disorders. Access through your

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BEING VIEWED BY OTHERS CHRONIC IN VIVO IMAGING DEFINES AGE-DEPENDENT ALTERATIONS OF NEUROGENESIS IN THE MOUSE HIPPOCAMPUS Article Open access 20 February 2023 TRANSCRIPTIONAL AND EPIGENETIC

DYSREGULATION IMPAIRS GENERATION OF PROLIFERATIVE NEURAL STEM AND PROGENITOR CELLS DURING BRAIN AGING Article 04 January 2024 FORMATION AND INTEGRATION OF NEW NEURONS IN THE ADULT

HIPPOCAMPUS Article 25 February 2021 DATA AVAILABILITY All data generated in this study are included in this published article and its supplementary information files, which are available

from the corresponding author on reasonable request. The raw scRNA-seq data in this study have been submitted to the Genome Sequence Archive in Beijing Institute of Genomics (BIG) Data

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adult mouse hippocampus. STAR Protoc. 2021;2:100374. Article  CAS  PubMed  PubMed Central  Google Scholar  Download references FUNDING This research was supported by grants from

STI2030-Major Projects (2021ZD0202302 to WG), the National Science Foundation of China (32394030 and 82271202 to WG). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Neurology,

China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, 130033, China Ziqi Liang & Jinting He * State Key Laboratory for Molecular and Developmental Biology, Institute

of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China Ziqi Liang, Zhimin Li, Dan Zhang, Xing Luo, Qiang Liu, Dezhe Qin, Min Wang, Zhiheng Xu & 

Weixiang Guo * Graduate School, University of Chinese Academy of Sciences, Beijing, 100093, China Ziqi Liang, Zhimin Li, Dan Zhang, Dezhe Qin, Zhiheng Xu & Weixiang Guo * Department of

lmmunology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China Jin Feng Authors * Ziqi Liang View author publications You can also search for this author

inPubMed Google Scholar * Zhimin Li View author publications You can also search for this author inPubMed Google Scholar * Dan Zhang View author publications You can also search for this

author inPubMed Google Scholar * Xing Luo View author publications You can also search for this author inPubMed Google Scholar * Qiang Liu View author publications You can also search for

this author inPubMed Google Scholar * Dezhe Qin View author publications You can also search for this author inPubMed Google Scholar * Min Wang View author publications You can also search

for this author inPubMed Google Scholar * Zhiheng Xu View author publications You can also search for this author inPubMed Google Scholar * Jin Feng View author publications You can also

search for this author inPubMed Google Scholar * Jinting He View author publications You can also search for this author inPubMed Google Scholar * Weixiang Guo View author publications You

can also search for this author inPubMed Google Scholar CONTRIBUTIONS Ziqi Liang, Jinting He and Weixiang Guo conceived experiments; Ziqi Liang performed the analysis, created figures and

drafted the manuscript. Zhimin Li, Jinting He, Jin Feng and Min Wang provided animals for the experiment, as well as interpretation of biological results. Xing Luo, Qiang Liu and Dezhe Qin

performed the behavioral tests, as well as interpretation of biological results. Dan Zhang and Zhiheng Xu performed the single cell-RNA-seq analysis. Weixiang Guo wrote the manuscript. All

authors read, revised, and approved the manuscript. CORRESPONDING AUTHORS Correspondence to Jinting He or Weixiang Guo. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no

competing interests. ETHICS APPROVAL AND CONSENT TO PARTICIPATE This study did not involve any human subjects. All animal care and related experimental procedures were conducted following

the highest ethical standards and were approved by the IGDB Institutional Animal Care and Use Committee. All animals were bred and raised by the Transgenic Mouse Facility at IGDB under a

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CITE THIS ARTICLE Liang, Z., Li, Z., Zhang, D. _et al._ Dual recombinase-mediated intersectional genetics defines the functional heterogeneity of neural stem cells in adult hippocampus.

_Mol Psychiatry_ (2025). https://doi.org/10.1038/s41380-025-02937-x Download citation * Received: 12 June 2024 * Revised: 15 January 2025 * Accepted: 18 February 2025 * Published: 24

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