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Peer-reviewedCC BYAdvanced science (Weinheim, Baden-Wurttemberg, Germany)

PBRM1 Deficiency in Microglia Leads to Excessive Neurogenesis and Autism-Like Behaviors via the CCL5-CCR1/5-β-catenin Signaling Axis.

  • Yang-Yang Duan1,2,3
  • Lin-Fei Jiao1,2,3
  • Pei-Pei Liu1,2,3
  • Chun-Hui Duan1,2,3
  • Xiao Li1,2,3
  • Zi-Han Zhang1,2,3
  • Yue-Qi Zhang1,2,3
  • Xin-Li Ouyang1,2,3
  • Hong-Zhen Du1,2,3
  • Sha Liu4
  • Yi Tang5
  • Zhao-Qian Teng1,2,3
1 more authors
  • Chang-Mei Liu1,2,3
5 affiliations
  1. 1State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  2. 2University of Chinese Academy of Sciences, Beijing, China.
  3. 3Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
  4. 4Center for Brain & Disease Research, VIB-KU Leuven, Leuven, Belgium.
  5. 5Department of Neurology, Innovation Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China.
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Abstract

The prevalence of autism spectrum disorder (ASD), a heterogeneous neurodevelopmental disorder with limited effective therapeutic drugs, has been rising worldwide. Missense mutations in Polybromo 1 (Pbrm1), a core component of the SWI/SNF (switch/sucrose non-fermentable) chromatin remodeling complex, have been identified as a risk factor for ASD; however, whether PBRM1 loss of function contributes to the pathogenesis remains elusive. Here we provide direct evidence that microglial PBRM1 deficiency leads to altered microglial clusters, excessive neurogenesis, and ASD-like behaviors in mice. Integrated molecular analyses reveal that PBRM1 directly binds to the Ccl5 promoter and represses the expression of CCL5. Elevated CCL5 promotes the proliferation and neuronal differentiation of neural stem/progenitor cells (NSPCs) via the CCR1/5-β-catenin signaling pathway. Importantly, pharmacological blockade of CCR1/5 ameliorates behavioral deficits in Pbrm1 cKO mice. Together, these findings identify a previously unrecognized microglia-NSPC communication mechanism linking PBRM1 dysfunction to aberrant neurodevelopment and suggest the CCL5-CCR1/5 axis as a potential therapeutic target for ASD.

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Cite

BibTeXRIS
BibTeX
@article{duan2026pbrm1,
  title = {{PBRM1 Deficiency in Microglia Leads to Excessive Neurogenesis and Autism-Like Behaviors via the CCL5-CCR1/5-β-catenin Signaling Axis.}},
  author = {Yang-Yang Duan and Lin-Fei Jiao and Pei-Pei Liu and Chun-Hui Duan and Xiao Li and Zi-Han Zhang and Yue-Qi Zhang and Xin-Li Ouyang and Hong-Zhen Du and Sha Liu and Yi Tang and Zhao-Qian Teng and Chang-Mei Liu},
  journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78086},
  url = {https://europepmc.org/article/MED/42893407},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - PBRM1 Deficiency in Microglia Leads to Excessive Neurogenesis and Autism-Like Behaviors via the CCL5-CCR1/5-β-catenin Signaling Axis.
AU  - Yang-Yang Duan
AU  - Lin-Fei Jiao
AU  - Pei-Pei Liu
AU  - Chun-Hui Duan
AU  - Xiao Li
AU  - Zi-Han Zhang
AU  - Yue-Qi Zhang
AU  - Xin-Li Ouyang
AU  - Hong-Zhen Du
AU  - Sha Liu
AU  - Yi Tang
AU  - Zhao-Qian Teng
AU  - Chang-Mei Liu
PY  - 2026
DA  - 2026/10/18
JO  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO  - 10.1002/advs.78086
UR  - https://europepmc.org/article/MED/42893407
AB  - The prevalence of autism spectrum disorder (ASD), a heterogeneous neurodevelopmental disorder with limited effective therapeutic drugs, has been rising worldwide. Missense mutations in Polybromo 1 (Pbrm1), a core component of the SWI/SNF (switch/sucrose non-fermentable) chromatin remodeling complex, have been identified as a risk factor for ASD; however, whether PBRM1 loss of function contributes to the pathogenesis remains elusive. Here we provide direct evidence that microglial PBRM1 deficiency leads to altered microglial clusters, excessive neurogenesis, and ASD-like behaviors in mice. Integrated molecular analyses reveal that PBRM1 directly binds to the Ccl5 promoter and represses the expression of CCL5. Elevated CCL5 promotes the proliferation and neuronal differentiation of neural stem/progenitor cells (NSPCs) via the CCR1/5-β-catenin signaling pathway. Importantly, pharmacological blockade of CCR1/5 ameliorates behavioral deficits in Pbrm1 cKO mice. Together, these findings identify a previously unrecognized microglia-NSPC communication mechanism linking PBRM1 dysfunction to aberrant neurodevelopment and suggest the CCL5-CCR1/5 axis as a potential therapeutic target for ASD.
SN  - 2198-3844
ER  -