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000270139 041__ $$aEnglish
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000270139 1001_ $$00000-0001-5182-7102$$aIoannidis, Valentin$$b0
000270139 245__ $$aDisrupted extracellular matrix and cell cycle genes in autism-associated Shank3 deficiency are targeted by lithium.
000270139 260__ $$aLondon$$bMacmillan$$c2024
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000270139 520__ $$aThe Shank3 gene encodes the major postsynaptic scaffolding protein SHANK3. Its mutation causes a syndromic form of autism spectrum disorder (ASD): Phelan-McDermid Syndrome (PMDS). It is characterized by global developmental delay, intellectual disorders (ID), ASD behavior, affective symptoms, as well as extra-cerebral symptoms. Although Shank3 deficiency causes a variety of molecular alterations, they do not suffice to explain all clinical aspects of this heterogenic syndrome. Since global gene expression alterations in Shank3 deficiency remain inadequately studied, we explored the transcriptome in vitro in primary hippocampal cells from Shank3∆11(-/-) mice, under control and lithium (Li) treatment conditions, and confirmed the findings in vivo. The Shank3∆11(-/-) genotype affected the overall transcriptome. Remarkably, extracellular matrix (ECM) and cell cycle transcriptional programs were disrupted. Accordingly, in the hippocampi of adolescent Shank3∆11(-/-) mice we found proteins of the collagen family and core cell cycle proteins downregulated. In vitro Li treatment of Shank3∆11(-/-) cells had a rescue-like effect on the ECM and cell cycle gene sets. Reversed ECM gene sets were part of a network, regulated by common transcription factors (TF) such as cAMP responsive element binding protein 1 (CREB1) and β-Catenin (CTNNB1), which are known downstream effectors of synaptic activity and targets of Li. These TFs were less abundant and/or hypo-phosphorylated in hippocampi of Shank3∆11(-/-) mice and could be rescued with Li in vitro and in vivo. Our investigations suggest the ECM compartment and cell cycle genes as new players in the pathophysiology of Shank3 deficiency, and imply involvement of transcriptional regulators, which can be modulated by Li. This work supports Li as potential drug in the management of PMDS symptoms, where a Phase III study is ongoing.
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000270139 650_7 $$2NLM Chemicals$$aShank3 protein, mouse
000270139 650_7 $$2NLM Chemicals$$aNerve Tissue Proteins
000270139 650_7 $$2NLM Chemicals$$abeta Catenin
000270139 650_7 $$2NLM Chemicals$$aCreb1 protein, mouse
000270139 650_7 $$2NLM Chemicals$$aCyclic AMP Response Element-Binding Protein
000270139 650_7 $$2NLM Chemicals$$aCTNNB1 protein, mouse
000270139 650_7 $$09FN79X2M3F$$2NLM Chemicals$$aLithium
000270139 650_7 $$2NLM Chemicals$$aMicrofilament Proteins
000270139 650_2 $$2MeSH$$aAnimals
000270139 650_2 $$2MeSH$$aNerve Tissue Proteins: genetics
000270139 650_2 $$2MeSH$$aNerve Tissue Proteins: metabolism
000270139 650_2 $$2MeSH$$aHippocampus: metabolism
000270139 650_2 $$2MeSH$$aExtracellular Matrix: metabolism
000270139 650_2 $$2MeSH$$aMice
000270139 650_2 $$2MeSH$$aMice, Knockout
000270139 650_2 $$2MeSH$$abeta Catenin: metabolism
000270139 650_2 $$2MeSH$$abeta Catenin: genetics
000270139 650_2 $$2MeSH$$aChromosome Disorders: genetics
000270139 650_2 $$2MeSH$$aChromosome Disorders: metabolism
000270139 650_2 $$2MeSH$$aChromosome Deletion
000270139 650_2 $$2MeSH$$aCell Cycle: drug effects
000270139 650_2 $$2MeSH$$aCell Cycle: genetics
000270139 650_2 $$2MeSH$$aAutistic Disorder: genetics
000270139 650_2 $$2MeSH$$aAutistic Disorder: metabolism
000270139 650_2 $$2MeSH$$aChromosomes, Human, Pair 22: genetics
000270139 650_2 $$2MeSH$$aCyclic AMP Response Element-Binding Protein: metabolism
000270139 650_2 $$2MeSH$$aCyclic AMP Response Element-Binding Protein: genetics
000270139 650_2 $$2MeSH$$aMale
000270139 650_2 $$2MeSH$$aTranscriptome: genetics
000270139 650_2 $$2MeSH$$aAutism Spectrum Disorder: genetics
000270139 650_2 $$2MeSH$$aAutism Spectrum Disorder: metabolism
000270139 650_2 $$2MeSH$$aAutism Spectrum Disorder: drug therapy
000270139 650_2 $$2MeSH$$aMice, Inbred C57BL
000270139 650_2 $$2MeSH$$aLithium: pharmacology
000270139 650_2 $$2MeSH$$aMicrofilament Proteins: metabolism
000270139 650_2 $$2MeSH$$aMicrofilament Proteins: genetics
000270139 650_2 $$2MeSH$$aCells, Cultured
000270139 7001_ $$aPandey, Rakshita$$b1
000270139 7001_ $$aBauer, Helen Friedericke$$b2
000270139 7001_ $$aSchön, Michael$$b3
000270139 7001_ $$aBockmann, Jürgen$$b4
000270139 7001_ $$0P:(DE-2719)2812855$$aBoeckers, Tobias M$$b5
000270139 7001_ $$00000-0002-3972-2057$$aLutz, Anne-Kathrin$$b6
000270139 773__ $$0PERI:(DE-600)1502531-7$$a10.1038/s41380-023-02362-y$$gVol. 29, no. 3, p. 704 - 717$$n3$$p704 - 717$$tMolecular psychiatry$$v29$$x1359-4184$$y2024
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