Transcriptome analyses suggest minimal effects of Shank3 dosage on directional gene expression changes in the mouse striatum|RISS 상세보기

다국어 초록 (Multilingual Abstract)

Both deletions and duplications of the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene, encoding excitatory postsynaptic scaffolds, are causally associated with various brain disorders, suggesting that proper Shank3 dosage is critical for normal brain development and function. In addition to its well-established synaptic functions, recent studies have suggested that Shank3 can also affect gene expression in the nucleus. However, it has not been investigated whether there are a group of genes whose directional expression is regulated in a Shank3 dosagedependent manner (i.e. showing opposite changes in expression following Shank3 reduction and overexpression). This is an important issue to be examined for better understanding why neuronal development and function are sensitive to Shank3 dosage, and how much transcriptional changes contribute to neuronal phenotypes affected by Shank3 dosage. To examine this, we performed transcriptome analyses on the striatum of Shank3 heterozygous and knock-out mice, which identified three and 17 differentially expressed genes, respectively. We then compared the results to those of our previous striatal transcriptome analysis of Shank3 overexpressing mice and identified 31 candidate genes showing directional expression changes in a Shank3 dosage-dependent manner. However, overall, their Shank3 dosage-dependent fold changes were very subtle (average of absolute log2(fold change) was 0.139). Meanwhile, the gene set enrichment analyses of the striatal transcriptome suggested that Shank3 dosage may affect anchoring junction-related functions. Taken together, these results suggest that Shank3 dosage minimally affects directional gene expression changes in the mouse striatum.

번역하기

참고문헌 (Reference)

1 Jin C, "Transcriptome analysis of Shank3-overexpressing mice reveals unique molecular changes in the hypothalamus" 11 : 71-, 2018

2 Sheng M, "The Shank family of scaffold proteins" 113 (113): 1851-1856, 2000

3 Grabrucker S, "The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation" 253 : 126-137, 2014

4 Huang da W, "Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources" 4 : 44-57, 2009

5 Lee Y, "Striatal transcriptome and interactome analysis of Shank3-overexpressing mice reveals the connectivity between Shank3 and mTORC1 signaling" 10 : 201-, 2017

6 Qin L, "Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase(HDAC)inhibition" 21 : 564-575, 2018

7 Peca J, "Shank3 mutant mice display autistic-like behaviours and striatal dysfunction" 472 : 437-442, 2011

8 Patro R, "Salmon provides fast and bias-aware quantification of transcript expression" 14 : 417-419, 2017

9 Han K, "SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties" 503 : 72-77, 2013

10 Monteiro P, "SHANK proteins : roles at the synapse and in autism spectrum disorder" 18 : 147-157, 2017