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Opposite phenotypic effects and genetic dosage in mouse models of 16p11.2 deletion and duplication syndromes

ABSTRACT: The 16p11.2 deletion and duplication syndromes have been associated with developmental delay and autism spectrum disorders, and a reciprocal effect on body mass index. Here we explored these links with new engineered mouse models carrying a deletion (Del/+) and duplication (Dup/+) of the whole 16p11.2 homologous Sult1a1-Spn region. On a pure genetic background, compared to wild-types, Del/+ mice carrying the deletion showed weight and adipogenesis deficits, hyperactivity, repetitive behaviors, and recognition memory deficits, whereas Dup/+ mice showed the opposite phenotypes and Del/Dup individuals displayed no changes. Alterations in social interaction were also observed in Del/+ and Dup/+ animals on a mixed genetic background. Transcriptomic analysis revealed that the majority of genes located on the Sult1a1-Spn were dosage-sensitive and potentially implicated in the opposite phenotypes described above on the neurocognitive aspect. Nevertheless, the outcome of the 16p11 region genetic dosage on metabolism depends on different genetic contributions between human and mouse.

ORGANISM(S): Mus musculus

PROVIDER: GSE66468 | GEO | 2015/11/18

SECONDARY ACCESSION(S): PRJNA277022

REPOSITORIES: GEO

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Excitatory dysfunction drives network and calcium handling deficits in 16p11.2 duplication schizophrenia iPSC-derived neurons

Project description:Background - Schizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human iPSC-derived neurons (iNs) has emerged as a promising strategy. Copy number variations (CNV) confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing risk 14.5 fold. Methods - To dissect the contribution of excitatory (iENs) versus GABAergic (iGNs) neurons to SCZ pathophysiology, we induced iNs from CRISPR-Cas9 engineered isogenic and SCZ patient-derived iPSCs, and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures. Results - In iEN/iGN cocultures, we found reduced neuronal network firing rate and synchrony at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for excitatory neurons. Transcriptomic analysis of isogenic 16p11.2 duplication (DUP) iENs revealed pathway dysregulation related to neuroarchitecture and calcium ion binding. Consistent with this, isogenic DUP iENs showed reduced dendrite length and calcium imaging revealed deficits in calcium handling. Analysis of iENs from 16p11.2 duplication-carrying SCZ patients (SCZ) revealed overlapping deficits in network synchrony, dendrite arborization and calcium handling. Conclusions - Our results indicate 16p11.2 duplication-dependent alterations to SCZ neurodevelopment. Calcium ion binding was the only altered transcriptomic gene set shared between isogenic and patient-derived iENs, suggesting a central role of calcium signaling in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers and supports network synchrony and calcium handling as outcomes directly linked to this genetic mutation.

2022-10-13 | GSE215183 | GEO

Mus musculus

Project description:Opposite phenotypic effects and genetic dosage in mouse models of 16p11.2 deletion and duplication syndromes

| PRJNA277022 | 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 [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

SNP chip data of MCL

Project description:Mantle cell lymphoma (MCL) is a lymphoma characterized by aberrant activation of CCND1/cyclin D1 followed by sequential genetic abnormalities. Genomic abnormalities in MCL have been extensively examined by classical cytogenetics and microarray-based comparative genomic hybridization techniques, pointing out a number of alterations in genomic regions that correlate with the neoplastic phenotype and survival. Recently, single nucleotide polymorphism genomic microarrays (SNP-chip) have been developed and used for analysis of cancer genomics. This technique allows detection of genomic changes with higher resolution, including loss of heterozygosity without changes of gene dosage, so-called acquired uniparental disomy (aUPD). As a result of the analysis, known alterations were confirmed by SNP arrays, including deletion of INK4A/ARF, duplication/amplification of MYC, deletion of ATM, and deletion of TP53. We also identified a duplication/amplification that occurred at 13q involving oncogenic microRNA, miR17-92. We found other genomic abnormalities, including duplication/amplification of cyclin D1, del(1p), del(6q), dup(3q) and dup(18q). Our SNP-chip analysis detected these abnormalities at high resolution, allowing us to narrow the size of the commonly deleted regions, including 1p and 6q. Our SNP-chip analysis detected a number of aUPD sites, including whole chromosome 9 aUPD and 9p aUPD. We also found an MCL case with 19p, leading to homozygous deletion of TNFSF genes. keyword: SNP-chip; Kawmata_MCL

2009-11-13 | GSE18820 | GEO

Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition.

Project description:Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches.

2017-04-14 | GSE80311 | GEO

Cerebral organoids model neocortical development disrupted by 16p11.2 CNV in autism

Project description:The 16p11.2 is the most common copy number variant (CNV) associated with Autism Spectrum Disorder (ASD). We used patient-derived cerebral organoids to investigate neurodevelopmental pathways dysregulated by dosage changes of 16p11.2 CNV. To investigate molecular dysregulation in DEL and DUP organoids, we carried out RNA sequencing and Tandem Mass Tag mass spectrometry (TMT-MS) on 1-month and 3-month organoids from the same samples. In proteomic analyses, we quantified a total of 6126 proteins in 1-month and 5481 proteins in 3-month organoids, with 13 and 11 proteins from within 16p11.2 CNV, respectively. Transcriptomic and proteomic profiling of organoids identifies the key drivers of functional effect by 16p11.2 CNV during neocortical development.

2019-12-19 | MSV000084727 | MassIVE

Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

Project description:Recurrent Copy Number Variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a ‘behavior trap’ phenotype—a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. Our findings indicate that 16p11.2 CNVs cause both brain and behavioral anomalies, providing new insight into human neurodevelopmental disorders.

2011-10-03 | GSE32012 | GEO

Cortical organoids model early brain development disrupted by 16p11.2 CNV in autism

Project description:Reciprocal deletion and duplication of 16p11.2 is the most common copy number variation (CNV) associated with Autism Spectrum Disorder (ASD) and other developmental disorders, and has significant effect on brain size. We used cortical organoids derived from ASD cases to investigate neurodevelopmental pathways dysregulated by dosage changes of 16p11.2 CNV. We show that organoids recapitulate patients’ macrocephaly and microcephaly phenotypes. Deletions and duplications have “mirror” effects on cell proliferation, maturation and synapse number, consistent with “mirror” effects on brain development in humans. Neuronal migration was decreased in both, deletion and duplication organoids. Transcriptomic and proteomic profiling revealed synaptic defects and neuronal migration as key drivers of 16p11.2 functional effect. We implicate upregulation of small GTPase RhoA involved in regulation of cytoskeletal dynamics, neuron migration and neurite outgrowth as one of the pathways impacted by the 16p11.2 CNV in ASD. Treatment with the RhoA inhibitor Rhosin rescued neuron migration, but not synaptic defects. This study identifies pathways dysregulated by the 16p11.2 CNV during early neocortical development using cortical organoid models. Grant ID: Simons Foundation, #345469 Grant Title: Translational dysregulation of the RhoA pathway in autism Affiliation: University of California San Diego Name: Lilia M. Iakoucheva; Alysson R. Muotri

2021-07-31 | GSE142174 | GEO

Inter-chromosomal contacts of the 16p11.2 locus connect with gene expression changes of Pcdh genes in autism spectrum disorder

Project description:Differentiation experiment of mouse embryonic stem cells (ESCs) to neuronal precursor (NPC) and immature dopaminergic neurons (NEU) commited to ventral midbrain lineage. Controls and mutant cell lines harboring heterozygous deletion (del) or duplication-deletion (dupdel) of 7qF3 locus which is synteny conserved with human 16p11.2 locus. Mice harbouring CNVs in this locus display behavioural phenotypes and distinct changes in brain architecture resembling ASD-like traits. Mouse models are described in Guy Horev et al., 2011 (doi: 10.1073/pnas.1114042108). Samples with same numeric identifier were differentiated in parallel.

2024-03-21 | GSE147239 | GEO

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