Project description:Shank3 is a core excitatory postsynaptic protein expressed in multiple brain regions including the medial prefrontal cortex, striatum, and hippocampus. Shank3 knock-out mice display autism-like behaviors and synaptic dysfunction. To understand molecular mechanisms underlying the behavioral and synaptic changes, we performed transcriptome (RNA-sequencing) analysis of the striatum tissues from 10 to 12-week-old wild-type and Shank3 knock-out/heterozygous mice.
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.
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.
Project description:Variants of the SH3 and multiple ankyrin repeat domains 3 (SHANK3), which encodes postsynaptic scaffolds, are associated with brain disorders. The targeted alleles in a few Shank3 knock-out (KO) lines contain a neomycin resistance (Neo) cassette, which may perturb the normal expression of neighboring genes; however, this has not been investigated in detail. We previously reported an unexpected increase in the mRNA expression of Shank3 exons 1~12 in the brains of Shank3B KO mice generated by replacing Shank3 exons 13~16 with the Neo cassette. In this study, we confirmed that the increased Shank3 mRNA in Shank3B KO brains produced an unusual ~60 kDa Shank3 isoform (Shank3-N), which did not properly localize to the synaptic compartment.
Project description:RNAseq analysis of USP7 conditional knock-out (cKO) mice. They were designed to flox exon 6 of USP7 and to allow deletion of exon 6 upon expression of Cre recombinase 27. USP7FL/FL mice were bred with Vav1-Cre mice to obtain USP7FL/wt-Vav1-Cre mice (heterozygote). USP7FL/FL-Vav1-Cre mice (homozygote) were obtained via breeding of heterozygous cKO mice.
Project description:Shank3 is a core excitatory postsynaptic protein enriched in the striatum. We have previously generated and characterized Shank3-overexpressing transgenic mice, and found that these mice exhibited manic-like behavioral phenotypes. To understand molecular mechanisms underlying the behavioral changes, we performed transcriptome (RNA-sequencing) analysis of the striatal tissues from 12-week-old wild-type and Shank3 transgenic mice.
Project description:Shank3 is a core excitatory postsynaptic protein expressed in multiple brain regions including the medial prefrontal cortex, striatum, and hippocampus. We have previously generated and characterized Shank3-overexpressing transgenic mice, and found that these mice exhibited manic-like behavioral phenotypes and increased food intake. To understand molecular mechanisms underlying the behavioral changes, we performed transcriptome (RNA-sequencing) analysis of the hypothalamic tissues from 10 to 12-week-old wild-type and Shank3 transgenic mice.
Project description:Shank3 is a core excitatory postsynaptic protein expressed in multiple brain regions including the medial prefrontal cortex, striatum, and hippocampus. We have previously generated and characterized Shank3-overexpressing transgenic mice, and found that these mice exhibited manic-like behavioral phenotypes. To understand molecular mechanisms underlying the behavioral changes, we performed transcriptome (RNA-sequencing) analysis of the mPFC tissues from 10 to 12-week-old wild-type and Shank3 transgenic mice.
Project description:Title: Comparison of ovarian gene expression in RIP140 wild type, heterozygous and knock out mice.<br/> Description: RIP140 null mice fail to ovulate. This experiment was designed to <br/> determine the gene expression profile of these animals compared <br/> to wild type and heterozygous animals following hormone treatments <br/> that induce the biological changes required for ovulation to occur.