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000285735 1001_ $$00009-0000-1072-6890$$aMa, Yuhua$$b0$$eFirst author
000285735 245__ $$aShank3 related oligodendrocyte alterations in autism are restored by Erk pathway inhibition.
000285735 260__ $$a[London]$$bSpringer Nature$$c2026
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000285735 520__ $$aWhite matter abnormalities are consistently observed in Shank3-related autism spectrum disorders (ASD), yet the mechanisms underlying oligodendrocyte dysfunction and myelination deficits remain poorly characterized. Here, we demonstrate that Shank3 deficiency disrupts oligodendrocyte development by promoting oligodendrocyte precursor cell (OPC) proliferation while impairing functional maturation and myelination. Mechanistically, Shank3 deficiency induced hyperactivation of the Erk signalling pathway, which compromised oligodendrocyte maturation and contributes to hypomyelination. Pharmacological inhibition of the Erk pathway effectively restored oligodendrocyte maturation in vitro, rescued myelination deficits in vivo, and partially improved autism-related behaviors and motor function in Shank3-deficient mice. Transcriptomic analyses furtherly revealed dysregulation of Wnt signalling, particularly the upregulation of Wnt5a, a key ligand of the non-canonical Wnt pathway, in Shank3-deficient oligodendrocytes. Consistently, Wnt5a treatment was found to activate Erk signalling in primary oligodendrocytes and replicate the observed myelination deficits. These findings uncover the Wnt5a-Erk axis as a critical regulator of oligodendrocyte dysfunction in Shank3-related ASD and highlight its therapeutic potential for addressing associated white matter deficits.
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000285735 650_7 $$2NLM Chemicals$$aShank3 protein, mouse
000285735 650_7 $$2NLM Chemicals$$aMicrofilament Proteins
000285735 650_7 $$2NLM Chemicals$$aNerve Tissue Proteins
000285735 650_2 $$2MeSH$$aAnimals
000285735 650_2 $$2MeSH$$aMale
000285735 650_2 $$2MeSH$$aMice
000285735 650_2 $$2MeSH$$aAutistic Disorder: genetics
000285735 650_2 $$2MeSH$$aAutistic Disorder: metabolism
000285735 650_2 $$2MeSH$$aAutistic Disorder: physiopathology
000285735 650_2 $$2MeSH$$aCorpus Callosum: metabolism
000285735 650_2 $$2MeSH$$aCorpus Callosum: physiopathology
000285735 650_2 $$2MeSH$$aMAP Kinase Signaling System
000285735 650_2 $$2MeSH$$aMice, Knockout
000285735 650_2 $$2MeSH$$aMolecular Targeted Therapy
000285735 650_2 $$2MeSH$$aMyelin Sheath: genetics
000285735 650_2 $$2MeSH$$aMyelin Sheath: metabolism
000285735 650_2 $$2MeSH$$aOligodendroglia: physiology
000285735 650_2 $$2MeSH$$aPrimary Cell Culture
000285735 650_2 $$2MeSH$$aWhite Matter: metabolism
000285735 650_2 $$2MeSH$$aWhite Matter: physiopathology
000285735 650_2 $$2MeSH$$aMicrofilament Proteins: deficiency
000285735 650_2 $$2MeSH$$aMicrofilament Proteins: genetics
000285735 650_2 $$2MeSH$$aNerve Tissue Proteins: deficiency
000285735 650_2 $$2MeSH$$aNerve Tissue Proteins: genetics
000285735 7001_ $$00009-0009-7483-137X$$aBauer, Helen Friedericke$$b1
000285735 7001_ $$aBockmann, Juergen$$b2
000285735 7001_ $$aSchön, Michael$$b3
000285735 7001_ $$0P:(DE-2719)2812855$$aBoeckers, Tobias M$$b4
000285735 7001_ $$00000-0002-3972-2057$$aLutz, Anne-Kathrin$$b5
000285735 773__ $$0PERI:(DE-600)1502531-7$$a10.1038/s41380-025-03333-1$$gVol. 31, no. 4, p. 1880 - 1897$$n4$$p1880 - 1897$$tMolecular psychiatry$$v31$$x1359-4184$$y2026
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