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Changes in social behaviour with alterations of MAPK3 and KCTD13/CUL3 pathways in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders [Sprague Dawley]

ABSTRACT: Changes in social behaviour with alterations of MAPK3 and KCTD13/CUL3 pathways in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders [Sprague Dawley]

PROVIDER: PRJNA933146 | ENA |

REPOSITORIES: ENA

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Changes in social behaviour with alterations of MAPK3 and KCTD13/CUL3 pathways in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders [Sprague Dawley]

Project description:Copy number variations (CNVs) of the human 16p11.2 locus are associated with several developmental/neurocognitive syndromes. Particularly, deletion and duplication of this genetic interval are found in patients with autism spectrum disorders, intellectual disability and other psychiatric traits. The high gene density associated with the region and the strong phenotypic variability of incomplete penetrance, make the study of the 16p11.2 syndromes extremely complex. To systematically study the effect of 16p11.2 CNVs and identify candidate genes and molecular mechanisms involved in the pathophysiology, mouse models were generated previously and showed learning and memory, and to some extent social deficits. To go further in understanding the social deficits caused by 16p11.2 syndromes, we engineered deletion and duplication of the homologous region to the human 16p11.2 genetic interval in two rat outbred strains, Sprague Dawley (SD) and Long Evans (LE). The 16p11.2 rat models displayed convergent defects in social behaviour and only a few cognitive defects. Interestingly major pathways affecting MAPK3 and CUL3 were found altered in the rat 16p11.2 models with additional changes in males compared to females. Altogether, the consequences of the 16p11.2 genetic region dosage on social behaviour are now found in three different species: humans, mice and rats. In addition, the rat models pointed to sexual dimorphism, with lower severity of phenotypes in rat females compared to male mutants. This phenomenon is also observed in humans. We are convinced that the two rat models will be key to further investigating social behaviour and understanding the brain mechanisms and specific brain regions that are key to controlling social behaviour.

2023-02-16 | GSE224935 | GEO

Changes in social behaviour with alterations of MAPK3 and KCTD13/CUL3 pathways in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders [Long Evans]

2023-02-18 | GSE225112 | GEO

Changes in social behaviour with alterations of MAPK3 and KCTD13/CUL3 pathways in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders

Project description:Changes in social behaviour with alterations of MAPK3 and KCTD13/CUL3 pathways in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders

| PRJNA934074 | ENA

Changes in social behaviour with alterations of MAPK3 and KCTD13/CUL3 pathways in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders [Long Evans]

Project description:Changes in social behaviour with alterations of MAPK3 and KCTD13/CUL3 pathways in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders [Long Evans]

| PRJNA933939 | ENA

Regulation of AMP synthesis by a KCTD13 ubiquitin ligase connects 16p11.2 deletion syndrome to a metabolic disorder with autistic features

Project description:Madison JM, Duong K, Vieux EF, Iqbal S, Requadt E, Udeshi ND, Fereshetian S, Lewis MC, Gomes AS, Pierce KA, Platt RJ, Zhang F, Campbell AJ, Lal D, Wagner FF, Clish CB, Carr SA, Scolnick EM, Cottrell JR. 2020. Genetic variation of KCTD13 at the 16p11.2 deletion locus and of CUL3 are linked with autism, suggesting that substrates of a CUL3-KCTD13 ubiquitin ligase complex may be involved in disease pathogenesis. By comparing neuronal ubiquitylomes of Kctd13 mutant (Kctd13-delta) and wild-type mouse neurons, we identified a novel substrate of the KCTD13 ligase: adenylosuccinate synthetase (ADSS), an enzyme that catalyzes the first step in AMP synthesis. We found increased ADSS levels in Kctd13-delta neurons, as well as increased levels of succinyl-adenosine (S-Ado), a purine metabolite downstream of ADSS. Intriguingly, elevated S-Ado levels are the hallmark of adenylosuccinate lyase deficiency, a metabolic disorder with autism and epilepsy phenotypes. Importantly, these increased S-Ado levels in Kctd13-delta neurons were restored by treatment with an ADSS inhibitor. Lastly, analysis and functionalization of human KCTD13 variants suggests that KCTD13 variation may contribute to altered ubiquitination of ADSS and dysregulation of purine metabolism. Our results suggest that accumulation of succinyl-AMP metabolites may contribute to autistic features of the 16p11.2 deletion syndrome and that reducing ADSS activity may be therapeutically beneficial for these patients.

2020-07-29 | MSV000085846 | MassIVE

RNA-seq from cortex and hippocampus of mice harboring heterozygous and homozygous deletion of Kctd13, as well as wild-type controls.

Project description:Modeling haploinsufficiency and complete knockout of Kctd13--a candidate contributory gene within the syntenic 16p11.2 copy number variation region--in mice. Transcriptome analyses from cortex and hippocampus highlighted the dysregulation of pathways important in neurodevelopment, the most significant of which was synaptic formation. Differential expression (DE) analyses of genes was performed by comparing heterozygous deletion mice samples to wild-type control littermates, and homozygous deletion samples to their wild-type control littermates, separately for both Hippocampus and Cortex tissues. DE analyses were performed using DESeq2 with surrogate variable analysis package in R/Bioconductor, sva (72, version 3.26.0).

2018-12-06 | E-MTAB-7398 | biostudies-arrayexpress

Changes in social behaviour with alterations of MAPK3 and KCTD13/CUL3 pathways in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-02-16 | GSE225135 | GEO

Changes in social behavior with MAPK2 and KCTD13/CUL3 pathways alterations in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders.

Project description:Copy number variations (CNVs) of the human 16p11.2 locus are associated with several developmental/neurocognitive syndromes. Particularly, deletion and duplication of this genetic interval are found in patients with autism spectrum disorders, intellectual disability and other psychiatric traits. The high gene density associated with the region and the strong phenotypic variability of incomplete penetrance, make the study of the 16p11.2 syndromes extremely complex. To systematically study the effect of 16p11.2 CNVs and identify candidate genes and molecular mechanisms involved in the pathophysiology, mouse models were generated previously and showed learning and memory, and to some extent social deficits. To go further in understanding the social deficits caused by 16p11.2 syndromes, we engineered deletion and duplication of the homologous region to the human 16p11.2 genetic interval in two rat outbred strains, Sprague Dawley (SD) and Long Evans (LE). The 16p11.2 rat models displayed convergent defects in social behavior and in the novel object test in male carriers from both genetic backgrounds. Interestingly major pathways affecting MAPK1 and CUL3 were found altered in the rat 16p11.2 models with additional changes in males compared to females. Altogether, the consequences of the 16p11.2 genetic region dosage on social behavior are now found in three different species: humans, mice and rats. In addition, the rat models pointed to sexual dimorphism with lower severity of phenotypes in rat females compared to male mutants. This phenomenon is also observed in humans. We are convinced that the two rat models will be key to further investigating social behavior and understanding the brain mechanisms and specific brain regions that are key to controlling social behavior.

| S-EPMC10350633 | biostudies-literature

Transcriptome Profiling of patients with 16p11.2 rearrangements

Project description:The 600kb BP4-BP5 16p11.2 CNV (copy number variant) is associated with neuroanatomical, neurocognitive and metabolic disorders. These recurrent rearrangements are associated with reciprocal phenotypes such as obesity and underweight, macro- and microcephaly, as well as autism spectrum disorder (ASD) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal CNVs in 16p11.2. The genome-wide transcript perturbations correlated with clinical endophenotypes of the CNV and were enriched for genes associated with ASD. We uncovered a significant correlation between copy number changes and expression levels of genes mutated in ciliopathies. Transcriptome profiles of lymphoblastoid cell lines of 50 16p11.2 deletion carriers, 31 16p11.2 duplication carriers and 17 controls.

2015-05-10 | E-GEOD-57802 | biostudies-arrayexpress

Characterization of human iPSC-derived dopaminergic neurons with 16p11.2 CNVs

Project description:We studied human induced pluripotent stem cells (iPSCs)-derived dopaminergic (DA) neuron populations carrying CNVs of 16p11.2 duplication and 16p11.2 deletion. Previously, healthy human iPSCs were edited using CRISPR-Cas9 method to produce isogenic lines with 16p11.2 deletion or 16p11.2 duplication. We differentiated these isogenic iPSC lines into neural precursor cells and dopaminergic neurons and collected RNA samples for gene expression analyses with RNA sequencing. Our aim was to identify differences in the expression of synaptic markers, neuronal differentiation markers, and neuron specific receptors that affect functionality of the neurons with 16p11.2 CNVs compared to isogenic control lines. We also studied physiological properties of these isogenic iPSC-derived DA neurons with 16p11.2 CNVs. In addition, we studied expression and activation of a specific molecular pathway KCTD13-RHOA in the iPSC derived DA neuron populations with 16p11.2 CNVs.

| EGAS00001005137 | EGA

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