The neurobiology of mouse models syntenic to human chromosome 15q

Takumi, Toru

doi:10.1007/s11689-011-9088-1

Cited by 25 publications

(20 citation statements)

References 124 publications

(159 reference statements)

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“…As shown in Fig. S1, there is excellent synteny between this region of human chromosome 15 and region 7p of mouse chromosome 7 [35]. One of these mouse models carries a 299 bp deletion within the Ube3a gene on the maternal chromosome 7 that confers a null mutation (herein called U-m-/p+)[8].…”

Section: Resultsmentioning

confidence: 99%

Ube3a Imprinting Impairs Circadian Robustness in Angelman Syndrome Models

et al. 2015

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Summary Background The paternal allele of Ube3a is silenced by imprinting in neurons, and Angelman Syndrome (AS) is a disorder arising from a deletion or mutation of the maternal Ube3a allele, which thereby eliminates Ube3a neuronal expression. Sleep disorders such as short sleep duration and increased sleep onset latency are very common in AS. Results We found an unique link between neuronal imprinting of Ube3a and circadian rhythms in two mouse models of AS, including enfeebled circadian activity behavior and slowed molecular rhythms in ex vivo brain tissues. As a consequence of compromised circadian behavior, metabolic homeostasis is also disrupted in AS mice. Unsilencing the paternal Ube3a allele restores functional circadian periodicity in neurons deficient in maternal Ube3a, but does not affect periodicity in peripheral tissues that are not imprinted for uniparental Ube3a expression. The ubiquitin ligase encoded by Ube3a interacts with the central clock components BMAL1 and BMAL2. Moreover, inactivation of Ube3a expression elevates BMAL1 levels in brain regions that control circadian behavior of AS model mice, indicating an important role for Ube3a in modulating BMAL1 turnover. Conclusions Ube3a expression constitutes a direct mechanistic connection between symptoms of a human neurological disorder and the central circadian clock mechanism. The lengthened circadian period leads to delayed phase, which could explain the short sleep duration and increased sleep onset latency of AS subjects. Moreover, we report the pharmacological rescue of an AS phenotype, in this case, altered circadian period. These findings reveal potential treatments for sleep disorders in AS patients.

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Section: Resultsmentioning

confidence: 99%

Ube3a Imprinting Impairs Circadian Robustness in Angelman Syndrome Models

et al. 2015

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“…UBE3A is located on the human chromosome 15q11-q13 region and copy number variations in this gene have been implicated in two neurological disorders other than AS: Prader-Willi syndrome (PWS) and ASD (75). Paternally-or maternallyinherited deletions of 15q11-q13 occur quite frequently and manifest as PWS or AS, respectively.…”

Section: Discussionmentioning

confidence: 99%

UBE3A regulates the transcription of IRF, an antiviral immunity

Furumai

Tamada

Liu

et al. 2019

Human Molecular Genetics

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UBE3A is a gene responsible for the pathogenesis of Angelman syndrome (AS), a neurodevelopmental disorder characterized by symptoms such as intellectual disability, delayed development and severe speech impairment. UBE3A encodes an E3 ubiquitin ligase, for which several targets have been identified, including synaptic molecules. Although proteolysis mainly occurs in the cytoplasm, UBE3A is localized to the cytoplasm and the nucleus. In fact, UBE3A is also known as a transcriptional regulator of the family of nuclear receptors. However, the function of UBE3A in the nucleus remains unclear. Therefore, we examined the involvement of UBE3A in transcription in the nuclei of neurons. Genome-wide transcriptome analysis revealed an enrichment of genes downstream of interferon regulatory factor (IRF) in a UBE3A-deficient AS mouse model. In vitro biochemical analyses further demonstrated that UBE3A interacted with IRF and, more importantly, that UBE3A enhanced IRF-dependent transcription. These results suggest a function for UBE3A as a transcriptional regulator of the immune system in the brain. These findings also provide informative molecular insights into the function of UBE3A in the brain and in AS pathogenesis.

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“…Chromosome 15q11–q13 is not only a recombination hotspot in the human genome, but also a well-known imprinting locus. Genomic alterations of this region are associated with several disorders, including autism spectrum disorder (ASD), Prader–Willi syndrome and Angelman syndrome [1] , [2] , [3] . In particular, the duplication of this region is the most common cytogenetic abnormality leading to ASD, a neurodevelopmental disorder characterized by social impairments, restricted interest and repetitive behaviors [4] .…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

Transcriptome profiling of white adipose tissue in a mouse model for 15q duplication syndrome

et al. 2015

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Obesity is not only associated with unhealthy lifestyles, but also linked to genetic predisposition. Previously, we generated an autism mouse model (patDp/+) that carries a 6.3 Mb paternal duplication homologous to the human 15q11–q13 locus. Chromosomal abnormalities in this region are known to cause autism spectrum disorder, Prader–Willi syndrome, and Angelman syndrome in humans. We found that, in addition to autistic-like behaviors, patDp/+ mice display late-onset obesity and hypersensitivity to a high-fat diet. These phenotypes are likely to be the results of genetic perturbations since the energy expenditures and food intakes of patDp/+ mice do not significantly differ from those of wild-type mice. Intriguingly, we found that an enlargement of adipose cells precedes the onset of obesity in patDp/+ mice. To understand the underlying molecular networks responsible for this pre-obese phenotype, we performed transcriptome profiling of white adipose tissue from patDp/+ and wild-type mice using microarray. We identified 230 genes as differentially expressed genes. Sfrp5 — a gene whose expression is positively correlated with adipocyte size, was found to be up-regulated, and Fndc5, a potent inducer of brown adipogenesis was identified to be the top down-regulated gene. Subsequent pathway analysis highlighted a set of 35 molecules involved in energy production, lipid metabolism, and small molecule biochemistry as the top candidate biological network responsible for the pre-obese phenotype of patDp/+. The microarray data were deposited in NCBI Gene Expression Omnibus database with accession number GSE58191. Ultimately, our dataset provides novel insights into the molecular mechanism of obesity and demonstrated that patDp/+ is a valuable mouse model for obesity research.

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The neurobiology of mouse models syntenic to human chromosome 15q

Cited by 25 publications

References 124 publications

Ube3a Imprinting Impairs Circadian Robustness in Angelman Syndrome Models

Ube3a Imprinting Impairs Circadian Robustness in Angelman Syndrome Models

UBE3A regulates the transcription of IRF, an antiviral immunity

Transcriptome profiling of white adipose tissue in a mouse model for 15q duplication syndrome

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