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

Molecular Psychiatry volume 30, pages 3516–3532 (2025)Cite this article

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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.

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Fig. 1: α- and β-rNSCs differently contribute to adult hippocampal neurogenesis.
Fig. 2: α- and β-rNSCs behave differently with age.
Fig. 3: Transcriptome analysis identify Prmt1 as an important regulatory element to specifically regulate the neurogenic potential of β-NSCs.
Fig. 4: PRMT1 plays distinct functions in α- and β-rNSCs.
Fig. 5: Pharmacological inhibition of PRMT1 restores age-related cognitive decline.
Fig. 6: PRMT1 inhibition combined with increased BDNF levels pharmacologically ameliorates cognitive functions in APP/PS1 mice.

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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 Center (https://bigd.big.ac.cn/gsa) under accession number CRA012491.

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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).

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Authors and Affiliations

  1. Department of Neurology, China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, 130033, China

    Ziqi Liang & Jinting He

  2. 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

  3. Graduate School, University of Chinese Academy of Sciences, Beijing, 100093, China

    Ziqi Liang, Zhimin Li, Dan Zhang, Dezhe Qin, Zhiheng Xu & Weixiang Guo

  4. Department of lmmunology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China

    Jin Feng

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  1. Ziqi Liang
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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.

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The authors declare no competing interests.

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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 regular light/dark (12 h/12 h) cycle with ad libitum access to food and water.

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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 30, 3516–3532 (2025). https://doi.org/10.1038/s41380-025-02937-x

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