Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the RORβ knockout

Masana, Monica I.; Sumaya, Isabel C.; Becker‐André, Michael; Dubocovich, Margarita L.

doi:10.1152/ajpregu.00687.2006

Cited by 63 publications

(51 citation statements)

References 42 publications

(57 reference statements)

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“…28,29 It should be noted that homozygous Rorb knockout mice exhibit retinal degeneration, modified circadian activity, less anxiety-related behavior, and ataxia but unprovoked seizure was not reported so far. 30,31 Such a possible divergence has already been observed for many other genes involved in neurodevelopmental disorders and is representative of the complexity of the human CNS, insufficiently modeled in rodents.…”

Section: Discussionmentioning

confidence: 91%

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

et al. 2016

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Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C4T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T4C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.

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Section: Discussionmentioning

confidence: 91%

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

et al. 2016

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“…3a and b). On the other hand, in the additional PFL, the activator promotes the transcription of Rors (mammals) [109][110][111][112] or Pdp1 (Drosophila) [107], which upregulates the transcription of the activator (Figs. 3a and b).…”

Section: Robust Designs Of Interlocked Transcriptional Feedback Loopsmentioning

confidence: 99%

“…In Drosophila, Pdp1ε knockdown or overexpression does not alter the circadian oscillation function [131]. Rorα, Rorβ and Rorα/γ mutant mice still show robust free-running with a slight change in period [109][110][111][112]. Recent studies show that these additional PFLs appear to function to regulate oscillator output rather than generating robust rhythms: Pdp1ε links the circadian clock output to the locomotor activity in Drosophila [131], and Rorγ plays a role for the circadian regulation of metabolic genes in mammals [110].…”

Section: Robust Designs Of Interlocked Transcriptional Feedback Loopsmentioning

confidence: 99%

Protein sequestration versus Hill‐type repression in circadian clock models

Kim¹

2016

IET syst. biol.

107

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Circadian (~24hr) clocks are self-sustained endogenous oscillators with which organisms keep track of daily and seasonal time. Circadian clocks frequently rely on interlocked transcriptionaltranslational feedback loops to generate rhythms that are robust against intrinsic and extrinsic perturbations. To investigate the dynamics and mechanisms of the intracellular feedback loops in circadian clocks, a number of mathematical models have been developed. The majority of the models use Hill functions to describe transcriptional repression in a way that is similar to the Goodwin model. Recently, a new class of models with protein sequestration-based repression has been introduced. Here, we discuss how this new class of models differs dramatically from those based on Hill-type repression in several fundamental aspects: conditions for rhythm generation, robust network designs and the periods of coupled oscillators. Consistently, these fundamental properties of circadian clocks also differ among Neurospora, Drosophila, and mammals depending on their key transcriptional repression mechanisms (Hill-type repression or protein sequestration). Based on both theoretical and experimental studies, this review highlights the importance of careful modeling of transcriptional repression mechanisms in molecular circadian clocks.

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“…This modest phenotype may be due to partial compensation by RORβ, which is also highly expressed in the SCN with a circadian rhythm of expression similar to that of the Period gene transcripts (Sumi et al 2002). Genetic disruption of Rorβ increases the free-running period in mice (Andre et al 1998;Masana et al 2007). Rorγ mRNA is highly expressed in the periphery and cycles in selective tissues (Yang et al 2006).…”

Section: Nrs Within the Core Clockworkmentioning

confidence: 99%

Nuclear Receptors, Metabolism, and the Circadian Clock

Yang¹,

Lamia²,

Evans³

2007

Cold Spring Harbor Symposia on Quantitative Biology

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As ligand-dependent transcription factors, the nuclear receptor superfamily governs a remarkable array of rhythmic physiologic processes such as metabolism and reproduction. To provide a "molecular blueprint" for nuclear receptor function in circadian biology, we established a diurnal expression profile of all mouse nuclear receptors in critical metabolic tissues. Our finding of broad expression and tissue-specific oscillation of nuclear receptors along with their key target genes suggests that diurnal nuclear receptor expression may contribute to established rhythms in metabolic physiology and that nuclear receptors may be involved in coupling peripheral circadian clocks to divergent metabolic outputs. Conversely, nuclear receptors may serve peripheral clock input pathways, integrating signals from the light-sensing central clock in the suprachiasmatic nucleus and other environmental cues, such as nutrients and xenobiotics. Interplay between the core circadian clock and nuclear receptors may define a large-scale signaling network that links biological timing to metabolic physiology.

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Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the RORβ knockout

Cited by 63 publications

References 42 publications

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

Protein sequestration versus Hill‐type repression in circadian clock models

Nuclear Receptors, Metabolism, and the Circadian Clock

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