Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by persistent deficits in social communication and repetitive behaviors. Recent studies have indicated that heterozygous mutations in the mixed lineage leukemia 5 (MLL5) gene are implicated in ASD susceptibility and associated with neurodevelopmental abnormalities. However, the detailed mechanisms remain unclear. Here, we demonstrate that Mll5 haploinsufficiency in mice impairs microglial phagocytosis, drives neuronal hyperexcitability, and recapitulates core ASD-like behaviors. We also show that Mll5 acts as an epigenetic regulator, modulating microglial phagocytosis via the TREM2-SGK3-GSK3β signaling axis, which is associated with deficient glucose metabolism. Furthermore, microglia derived from individual with ASD exhibit parallel reductions in MLL5 expression and phagocytic function. By targeting this pathway, lithium chloride, a GSK3β inhibitor, rescues both microglial phagocytosis deficits and behavioral abnormalities in Mll5 haploinsufficienct mice. Our findings highlight MLL5’s critical role in ASD and its potential as a therapeutic target.
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Data availability
Gene expression profiling data have been deposited at the GEO database (GEO: GSE280750) and are publicly available as of the date of publication. Source data are provided with this paper.
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Acknowledgements
We thank Professor Lih Wen Deng for sharing the MLL5 antibody with us, and we thank all the participating subjects. This work was funded by the National Natural Science Foundation of China (82130040 (J.S.), 82288101 (J.S.), 82171530 (J.J.L.), 81801344 (J.J.L.)), the Youth Program of National Natural Science Foundation of China (82009Y3510 (Y.B.W.)), Nursing Science Research Fund of Peking University (TYZH2023002 (J.J.L.)), and the Fundamental Research Funds for the Central Universities (71006Y2557 (J.J.L.)).
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Y.B.W. conceived and designed the experiments. S.G., Q.L., X.L., Z.F., L.H., and N.Q. performed the experiments and analyzed the data. Y.B.W. was responsible for validation. M.J., A.Z., X.X.L., H.Z., H.Z.Z., J.Z., X.D., Y.Z., L.L., J.S., J.J.L., and Y.B.W. provided resources. S.G. wrote the manuscript. Y.B.W., J.J.L, J.S., and L.L. revised the manuscript. Y.B.W., J.J.L., supervised the project.
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Gao, S., Lin, Q., Liu, X. et al. Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling and recapitulates ASD-like behaviors in mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71922-x
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DOI: https://doi.org/10.1038/s41467-026-71922-x
