Altered circadian rhythms and sleep in a new Angelman Syndrome mouse model

Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a. Comparing newly generated mouse models for Ube3a down-regulation (models of Angelman syndrome) vs. Ube3a up-regulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. In contrast to previous reports, we find that Ube3a is imprinted in neurons of the suprachiasmatic nuclei, the pacemaking circadian brain locus. In addition, Ube3a-deficient mice lack the typical drop in wake late in the dark period and have blunted responses to sleep deprivation. Suppression of physical activity by light in Ube3a-deficient mice is not due to anxiety as measured by behavioral tests and stress hormones; quantification of stress hormones may serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced Ube3a gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms.

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Angelman Syndrome: Identification and Management

Neonatal Network The Journal of Neonatal Nursing ◽

10.1891/0730-0832.36.3.142 ◽

2017 ◽

Vol 36 (3) ◽

pp. 142-151 ◽

Cited By ~ 2

Author(s):

Daniela Bonello ◽

Francesca Camilleri ◽

Jean Calleja-Agius

Keyword(s):

Ubiquitin Ligase ◽

Angelman Syndrome ◽

Chromosomal Region ◽

Motor Pattern ◽

E3 Ubiquitin Ligase ◽

Genetic Mutations ◽

Maternal Allele ◽

Ube3a Gene ◽

Severe Clinical Picture ◽

Genetically Determined

AbstractAngelman syndrome (AS) is a neurobehavioral and genetically determined condition, which affects approximately 1 in 15,000 individuals. It is caused by various genetic mutations and deletions of the maternally-inherited UBE3A gene, on the 15q11-13 chromosomal region. The UBE3A gene, which encodes E3 ubiquitin ligase, shows tissue-specific imprinting, being expressed entirely from the maternal allele.The diagnosis of AS is confirmed either by methylation test or by mutation analysis. A more severe clinical picture is linked with the deletion phenotype.Patients with AS have a behavioral and motor pattern defined as “happy puppet” because it is characterized by puppet-like ataxic jerky movements; a happy, sociable disposition; and paroxysms of laughter.There is currently no cure for AS, and management is mainly symptomatic. Novel therapeutic options are directed toward the possibility of activating the silenced paternal copy of the UBE3A gene.

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GABA and epileptogenesis: comparing gabrb3 gene-deficient mice with Angelman syndrome in man

Epilepsy Research ◽

10.1016/s0920-1211(99)00046-7 ◽

1999 ◽

Vol 36 (2-3) ◽

pp. 123-132 ◽

Cited By ~ 47

Author(s):

Timothy M DeLorey ◽

Richard W Olsen

Keyword(s):

Angelman Syndrome ◽

Deficient Mice

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Disrupted circadian rhythms in VIP- and PHI-deficient mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00200.2003 ◽

2003 ◽

Vol 285 (5) ◽

pp. R939-R949 ◽

Cited By ~ 232

Author(s):

Christopher S. Colwell ◽

Stephan Michel ◽

Jason Itri ◽

Williams Rodriguez ◽

J. Tam ◽

...

Keyword(s):

Circadian Rhythms ◽

Wheel Running ◽

Activity Rhythm ◽

Activity Patterns ◽

Circadian System ◽

Diurnal Rhythms ◽

Constant Darkness ◽

Light Cycle ◽

Wild Type ◽

Deficient Mice

The related neuropeptides vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) are expressed at high levels in the neurons of the suprachiasmatic nucleus (SCN), but their function in the regulation of circadian rhythms is unknown. To study the role of these peptides on the circadian system in vivo, a new mouse model was developed in which both VIP and PHI genes were disrupted by homologous recombination. In a light-dark cycle, these mice exhibited diurnal rhythms in activity which were largely indistinguishable from wild-type controls. In constant darkness, the VIP/PHI-deficient mice exhibited pronounced abnormalities in their circadian system. The activity patterns started ∼8 h earlier than predicted by the previous light cycle. In addition, lack of VIP/PHI led to a shortened free-running period and a loss of the coherence and precision of the circadian locomotor activity rhythm. In about one-quarter of VIP/PHI mice examined, the wheel-running rhythm became arrhythmic after several weeks in constant darkness. Another striking example of these deficits is seen in the split-activity patterns expressed by the mutant mice when they were exposed to a skeleton photoperiod. In addition, the VIP/PHI-deficient mice exhibited deficits in the response of their circadian system to light. Electrophysiological analysis indicates that VIP enhances inhibitory synaptic transmission within the SCN of wild-type and VIP/PHI-deficient mice. Together, the observations suggest that VIP/PHI peptides are critically involved in both the generation of circadian oscillations as well as the normal synchronization of these rhythms to light.

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Cryptochromes regulate IGF-1 production and signaling through control of JAK2-dependent STAT5B phosphorylation

Molecular Biology of the Cell ◽

10.1091/mbc.e16-08-0624 ◽

2017 ◽

Vol 28 (6) ◽

pp. 834-842 ◽

Cited By ~ 14

Author(s):

Amol Chaudhari ◽

Richa Gupta ◽

Sonal Patel ◽

Nikkhil Velingkaar ◽

Roman Kondratov

Keyword(s):

Circadian Rhythms ◽

Circadian Clock ◽

Skeletal Muscles ◽

Cancer Metabolism ◽

Reduced Body ◽

Circadian Control ◽

Cell Growth And Proliferation ◽

Deficient Mice ◽

Igf Signaling

Insulin-like growth factor (IGF) signaling plays an important role in cell growth and proliferation and is implicated in regulation of cancer, metabolism, and aging. Here we report that IGF-1 level in blood and IGF-1 signaling demonstrates circadian rhythms. Circadian control occurs through cryptochromes (CRYs)—transcriptional repressors and components of the circadian clock. IGF-1 rhythms are disrupted in Cry-deficient mice, and IGF-1 level is reduced by 80% in these mice, which leads to reduced IGF signaling. In agreement, Cry-deficient mice have reduced body (∼30% reduction) and organ size. Down-regulation of IGF-1 upon Cry deficiency correlates with reduced Igf-1 mRNA expression in the liver and skeletal muscles. Igf-1 transcription is regulated through growth hormone–induced, JAK2 kinase–mediated phosphorylation of transcriptional factor STAT5B. The phosphorylation of STAT5B on the JAK2-dependent Y699 site is significantly reduced in the liver and skeletal muscles of Cry-deficient mice. At the same time, phosphorylation of JAK2 kinase was not reduced upon Cry deficiency, which places CRY activity downstream from JAK2. Thus CRYs link the circadian clock and JAK-STAT signaling through control of STAT5B phosphorylation, which provides the mechanism for circadian rhythms in IGF signaling in vivo.

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The ubiquitin ligase NEDD4-2/NEDD4L regulates both sodium homeostasis and fibrotic signaling to prevent end-stage renal disease

Cell Death and Disease ◽

10.1038/s41419-021-03688-7 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Jantina A. Manning ◽

Sonia S. Shah ◽

Andrej Nikolic ◽

Tanya L. Henshall ◽

Yeesim Khew-Goodall ◽

...

Keyword(s):

Kidney Disease ◽

Renal Disease ◽

Ubiquitin Ligase ◽

End Stage Renal Disease ◽

Epithelial Mesenchymal Transition ◽

Collecting Duct ◽

Mesenchymal Transition ◽

Stage Renal Disease ◽

End Stage ◽

Deficient Mice

AbstractKidney disease progression can be affected by Na+ abundance. A key regulator of Na+ homeostasis is the ubiquitin ligase NEDD4-2 and its deficiency leads to increased Na+ transport activity and salt-sensitive progressive kidney damage. However, the mechanisms responsible for high Na+ induced damage remain poorly understood. Here we show that a high Na+ diet compromised kidney function in Nedd4-2-deficient mice, indicative of progression toward end-stage renal disease. Injury was characterized by enhanced tubule dilation and extracellular matrix accumulation, together with sustained activation of both Wnt/β-catenin and TGF-β signaling. Nedd4-2 knockout in cortical collecting duct cells also activated these pathways and led to epithelial–mesenchymal transition. Furthermore, low dietary Na+ rescued kidney disease in Nedd4-2-deficient mice and silenced Wnt/β-catenin and TGF-β signaling. Our study reveals the important role of NEDD4-2-dependent ubiquitination in Na+ homeostasis and protecting against aberrant Wnt/β-catenin/TGF-β signaling in progressive kidney disease.

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Angelman Syndrome: An Autism Spectrum Disorder

Journal of Student Research ◽

10.47611/jsr.v6i2.399 ◽

2018 ◽

Vol 6 (2) ◽

pp. 56-60

Author(s):

Andrew J. Kennedy ◽

Jeffrey O. Henderson

Keyword(s):

Angelman Syndrome ◽

Motor Development ◽

Neurodevelopmental Disorders ◽

Muscle Tension ◽

Autism Spectrum ◽

Speech Impairment ◽

Social Lives ◽

Genetic Abnormalities ◽

Ube3a Gene ◽

Genetic Mechanisms

Neurodevelopmental disorders limit the mental, physical, and social lives of affected individuals and their families. These disorders are often related to genetic abnormalities having a distinct chromosomal location. The abnormalities can cause incorrect proteins to be formed or biochemical pathways to be blocked, predominately affecting brain development, but also having pleiotropic effects. Research into defining and correcting these genetic abnormalities is important to help distinguish between unique neurodevelopmental disorders so that proper clinical interventions are available for affected individuals. In the following review, Angelman syndrome, which results from UBE3A gene function being lost at maternal chromosome 15q11.2-q13, will be discussed. Angelman patients suffer from the defining characteristics of speech impairment, uncontrolled laughing and smiling, motor development issues, muscle tension, and possible ataxia. The genetic mechanisms of the disorder as well as possible therapies will be discussed, with future areas of research into genetic therapies to treat Angelman syndrome also put forth. Research into Angelman syndrome can provide an avenue for a clearer understanding of other neurodevelopmental disorders.

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Novel Insights into the Role of UBE3A in Regulating Apoptosis and Proliferation

Journal of Clinical Medicine ◽

10.3390/jcm9051573 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1573 ◽

Cited By ~ 3

Author(s):

Lilach Simchi ◽

Julia Panov ◽

Olla Morsy ◽

Yonatan Feuermann ◽

Hanoch Kaphzan

Keyword(s):

Angelman Syndrome ◽

Critical Role ◽

Embryonic Fibroblasts ◽

Ubiquitin E3 Ligase ◽

Proliferation And Apoptosis ◽

Ube3a Gene ◽

Ubiquitin Binding ◽

Molecular Effects ◽

Substrate Proteins

The UBE3A gene codes for a protein with two known functions, a ubiquitin E3-ligase which catalyzes ubiquitin binding to substrate proteins and a steroid hormone receptor coactivator. UBE3A is most famous for its critical role in neuronal functioning. Lack of UBE3A protein expression leads to Angelman syndrome (AS), while its overexpression is associated with autism. In spite of extensive research, our understanding of UBE3A roles is still limited. We investigated the cellular and molecular effects of Ube3a deletion in mouse embryonic fibroblasts (MEFs) and Angelman syndrome (AS) mouse model hippocampi. Cell cultures of MEFs exhibited enhanced proliferation together with reduced apoptosis when Ube3a was deleted. These findings were supported by transcriptome and proteome analyses. Furthermore, transcriptome analyses revealed alterations in mitochondria-related genes. Moreover, an analysis of adult AS model mice hippocampi also found alterations in the expression of apoptosis- and proliferation-associated genes. Our findings emphasize the role UBE3A plays in regulating proliferation and apoptosis and sheds light into the possible effects UBE3A has on mitochondrial involvement in governing this balance.

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