Dataset Information

GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders

ABSTRACT: Copy number variations at 7q11.23 cause neurodevelopmental disorders with shared and opposite manifestations. Deletion leads to Williams-Beuren syndrome (WBS), while duplication causes 7q11.23 microduplication syndrome (7Dup). Converging evidence indicates GTF2I, from the 7q11.23 locus, is a key mediator of the cognitive-behavioral phenotypes associated with WBS and 7Dup. Here we integrate molecular profiling of patient-derived cortical organoids (COs) and transgenic mouse models to dissect 7q11.23 disease mechanisms. Proteomic and transcriptomic profiling of COs revealed opposite dynamics of neural progenitor proliferation and transcriptional imbalances, leading to precocious excitatory neuron production in 7Dup. The accelerated excitatory neuron production in 7Dup COs could be rescued by GTF2I knockdown. Transgenic mice with Gtf2i duplication recapitulated early neuronal differentiation defects and ASD-like behaviors. Remarkably, inhibition of LSD1, a downstream effector of GTF2I, was sufficient to rescue ASD-like phenotypes. We propose that the GTF2I-LSD1 axis constitutes a molecular pathway amenable to therapeutic intervention.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: alessandro cuomo

LAB HEAD: Giuseppe Testa

PROVIDER: PXD036770 | Pride | 2024-01-26

REPOSITORIES: Pride

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Publications

<i>GTF2I</i> dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders.

López-Tobón Alejandro A Shyti Reinald R Villa Carlo Emanuele CE Cheroni Cristina C Fuentes-Bravo Patricio P Trattaro Sebastiano S Caporale Nicolò N Troglio Flavia F Tenderini Erika E Mihailovich Marija M Skaros Adrianos A Gibson William T WT Cuomo Alessandro A Bonaldi Tiziana T Mercurio Ciro C Varasi Mario M Osborne Lucy L Testa Giuseppe G

Science advances 20231129 48

Copy number variations at 7q11.23 cause neurodevelopmental disorders with shared and opposite manifestations. Deletion causes Williams-Beuren syndrome featuring hypersociability, while duplication causes 7q11.23 microduplication syndrome (7Dup), frequently exhibiting autism spectrum disorder (ASD). Converging evidence indicates <i>GTF2I</i> as key mediator of the cognitive-behavioral phenotypes, yet its role in cortical development and behavioral hallmarks remains largely unknown. We integrated ...[more]

PMID: 38019906

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Project description:Shank3 is an abundant excitatory postsynaptic scaffolding proteins implicated in various neurodevelopmental and psychiatric disorders, including ASD, Phelan-McDermid syndrome, intellectual disability, and schizophrenia. Shank3-mutant mice with a homozygous deletion of exons 14-16 (Shank3-HM mice) show ASD-like behavioral deficits and altered synaptic and neuronal functions, but little is known about how different ages, brain regions, and gene dosages contribute to transcriptomic phenotypes in these mice. Here, we performed RNA-Seq-based transcriptomic analyses of the prefrontal cortex, hippocampus, and striatum in adult Shank3 heterozygous- and homozygous-mutant mice. In addition, juvenile and adult Shank3 homozygous-mutant forebrain transcriptomes were compared. Juvenile and adult forebrain transcriptomes from Shank3 homozygous-mutant mice showed the patterns that are opposite and similar to those observed in ASD: reverse-ASD and ASD-like patterns, respectively. Here, the juvenile reverse-ASD pattern involved synaptic gene upregulations and ribosomal and mitochondrial downregulations, whereas the adult ASD-like pattern involved opposite changes. Gene set enrichment analyses (GSEA) of brain regional transcripts in adult Shank3-HT and Shank3-HM mice revealed that the cortical, hippocampal, and striatal transcripts show distinctly altered biological functions and ASD-related/risk gene expressions. The cortex and striatum display ASD-like patterns whereas the hippocampus displays reverse-ASD patterns. The cortical ASD-like pattern more strongly involves ASD-risk genes whereas the striatal ASD-like pattern more strongly involves astrocyte/microglia genes. Shank3-HT and Shank3-HM transcripts in a given brain region display largely similar patterns in biological functions and ASD-related/risk gene expressions, suggestive of small gene dosage effects. These results suggest that heterozygous and homozygous Shank3 deletions in mice lead to age, brain region, and gene dosage-differential transcriptomic changes.

Dataset Information

GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders

Publications

<i>GTF2I</i> dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders.

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