Age, brain region, and gene dosage-differential transcriptomic changes in Shank3-mutant mice

Yoo, Taesun; Yoo, Ye-Eun; Kang, Hyojin; Kim, Eunjoon

doi:10.3389/fnmol.2022.1017512

Cited by 13 publications

(10 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alterations in the expression of genes associated with ribosomes were found in other Shank3 KO mice. RNA-Seq analysis of transcripts from mouse Shank3 KO mice lacking exons 14-16 showed that genes associated with ribosomes change in opposite directions consistently across different brain regions (44). Another study found that the expression of ribosomal and ribosome-related genes was upregulated in striatum and mPFC of juvenile Shank3 +/ΔC mice, while in adult Shank3 overexpressing mice it was downregulated in the same brain regions (45) and upregulated in the hypothalamus (46).…”

Section: Discussionmentioning

confidence: 99%

Decreased expression of ribosomal protein Rpl3 contributes to behavioral deficits caused by Shank3 deficiency

Verpelli¹,

Giona²,

Beretta³

et al. 2023

Preprint

View full text Add to dashboard Cite

Mutations or deletions in the SHANK3 gene have been identified in up to 1% of autism spectrum disorder cases and are considered the main cause of neuropsychiatric symptoms of Phelan McDermid syndrome (PMS). While in the absence of Shank3, synaptic dysfunctions have been extensively described, other mechanisms through which Shank3 could regulate neuronal functions have not been clearly elucidated. Here, we reported that the ribosomal protein Rpl3 was downregulated in cortex and striatum of Shank3 KO mice and in neurons differentiated from hiPSCs derived from a PMS patient. Rpl3 is essential for ribosomal biogenesis and function and its reduced expression resulted in impaired protein synthesis in Shank3 KO mice that can be rescued by restoring its expression. Furthermore, we showed that chronic treatment with VU0409551, a potent and selective mGlu5 positive allosteric modulator, rescued Rpl3 expression and the resulting reduced protein synthesis, leading to a long-lasting improvement of behavioral deficits in Shank3 KO mice. Altogether, we suggest a new role for Shank3 in modulating ribosomal function and protein synthesis, and that restoring protein synthesis could be a strategy to correct Shank3 KO related behavioral phenotypes.

show abstract

Section: Discussionmentioning

confidence: 99%

Decreased expression of ribosomal protein Rpl3 contributes to behavioral deficits caused by Shank3 deficiency

Verpelli¹,

Giona²,

Beretta³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…SpliceAI 73 and SnpEff 74 were used to analyze splice variants and evaluate the pathogenic potential of stop-loss, stop-gain, and frameshift variants. This re-annotation identified 1,530 new SNVs across 55,000 cases pooled from ASD (11,986 ES; 923 WGS), BP (14,210 ES), and SCZ (27,648 ES) cohorts (Fig. 7M), resulting in the discovery of 27 stop-loss, 60 stop-gain, 52 frameshift, and 53 splice variants in SHANK3 considered potentially deleterious or PTVs using CIS annotation in disease subjects but not in controls.…”

Section: L)mentioning

confidence: 99%

Transcriptional Determinism and Stochasticity Contribute to the Complexity of Autism AssociatedSHANKFamily Genes

Lu,

Ni,

Suarez-Meade

et al. 2024

Preprint

View full text Add to dashboard Cite

Precision of transcription is critical because transcriptional dysregulation is disease causing. Traditional methods of transcriptional profiling are inadequate to elucidate the full spectrum of the transcriptome, particularly for longer and less abundant mRNAs. SHANK3 is one of the most common autism causative genes. Twenty-four Shank3 mutant animal lines have been developed for autism modeling. However, their preclinical validity has been questioned due to incomplete Shank3 transcript structure. We applied an integrative approach combining cDNA-capture and long-read sequencing to profile the SHANK3 transcriptome in human and mice. We unexpectedly discovered an extremely complex SHANK3 transcriptome. Specific SHANK3 transcripts were altered in Shank3 mutant mice and postmortem brains tissues from individuals with ASD. The enhanced SHANK3 transcriptome significantly improved the detection rate for potential deleterious variants from genomics studies of neuropsychiatric disorders. Our findings suggest the stochastic transcription of genome associated with SHANK family genes.

show abstract

“…Contradictory findings across these studies may be attributed to mutations of various Shank3 isoforms. This hypothesis is backed by recent transcriptomics investigating gene dosage-differential changes in the hippocampus of Shank3 mutant mice ( 161 ).…”

Section: Abnormalities In the Structure And Function Of The Hippocamp...mentioning

confidence: 99%

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder

Long,

Li,

Liu

et al. 2024

Front. Psychiatry

View full text Add to dashboard Cite

The hippocampus is one of the brain areas affected by autism spectrum disorder (ASD). Individuals with ASD typically have impairments in hippocampus-dependent learning, memory, language ability, emotional regulation, and cognitive map creation. However, the pathological changes in the hippocampus that result in these cognitive deficits in ASD are not yet fully understood. In the present review, we will first summarize the hippocampal involvement in individuals with ASD. We will then provide an overview of hippocampal structural and functional abnormalities in genetic, environment-induced, and idiopathic animal models of ASD. Finally, we will discuss some pharmacological and non-pharmacological interventions that show positive impacts on the structure and function of the hippocampus in animal models of ASD. A further comprehension of hippocampal aberrations in ASD might elucidate their influence on the manifestation of this developmental disorder and provide clues for forthcoming diagnostic and therapeutic innovation.

show abstract

Age, brain region, and gene dosage-differential transcriptomic changes in Shank3-mutant mice

Cited by 13 publications

References 67 publications

Decreased expression of ribosomal protein Rpl3 contributes to behavioral deficits caused by Shank3 deficiency

Decreased expression of ribosomal protein Rpl3 contributes to behavioral deficits caused by Shank3 deficiency

Transcriptional Determinism and Stochasticity Contribute to the Complexity of Autism AssociatedSHANKFamily Genes

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder

Contact Info

Product

Resources

About