Molecular Analysis of Sleep: Wake Cycles in<i>Drosophila</i>

Sehgal, Amita; Joiner, William J.; Crocker, Amanda; Koh, Kyunghee; Sathyanarayanan, Sriram; Fang, Yanshan; Wu, Mark N.; Williams, Julie; Zheng, X. Long

doi:10.1101/sqb.2007.72.018

Cited by 29 publications

(21 citation statements)

References 47 publications

(58 reference statements)

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“…These results are in agreement with the clinical observations that patients with FXS have attention deficit hyperactivity disorder (ADHD) (Hagerman 1997;Torrioli et al 2008). Analysis of the circadian molecular clock revealed that cycling of the two key elements of the circadian clock PER and TIM proteins and their respective mRNA levels are not affected in dFmr1 mutants (Dockendorff et al 2002;Inoue et al 2002;Morales et al 2002;HelfrichForster 2005;Chang 2006;Sehgal et al 2007). However, the eclosion rhythm, which is controlled by the circadian system, is affected in dFmr1 mutant flies and the circadian oscillation of cAMP response element binding protein (CREB), a known output of the circadian clock in Drosophila (Belvin et al 1999), is dramatically affected in dFmr1 mutant flies (Dockendorff et al 2002;Morales et al 2002).…”

Section: Dfmr1 Mutant Flies Have Abnormal Circadian Rhythmssupporting

confidence: 80%

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

2014

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The Fragile X syndrome (FXS) is the most frequent form of inherited mental disability and is considered a monogenic cause of autism spectrum disorder. FXS is caused by a triplet expansion that inhibits the expression of the FMR1 gene. The gene product, the Fragile X Mental Retardation Protein (FMRP), regulates mRNA metabolism in brain and nonneuronal cells. During brain development, FMRP controls the expression of key molecules involved in receptor signaling, cytoskeleton remodeling, protein synthesis and, ultimately, spine morphology. Symptoms associated with FXS include neurodevelopmental delay, cognitive impairment, anxiety, hyperactivity, and autistic-like behavior. Twenty years ago the first Fmr1 KO mouse to study FXS was generated, and several years later other key models including the mutant Drosophila melanogaster, dFmr1, have further helped the understanding of the cellular and molecular causes behind this complex syndrome. Here, we review to which extent these biological models are affected by the absence of FMRP, pointing out the similarities with the observed human dysfunction. Additionally, we discuss several potential treatments under study in animal models that are able to partially revert some of the FXS abnormalities.

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Section: Dfmr1 Mutant Flies Have Abnormal Circadian Rhythmssupporting

confidence: 80%

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

2014

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“…Although locomotor activity is the best-characterized circadian output, the circadian clock regulates numerous other outputs such as sleep (13)(14)(15)(16), neuronal activity in olfactory neurons (17), and metabolism (18), and a number of tissues have been found to harbor autonomous clocks (19). This poses the question of the nature of the output genes that mediate these processes.…”

mentioning

confidence: 99%

The circadian output gene takeout is regulated by Pdp1ε

Benito

Hoxha

Lama

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The circadian clock controls many circadian outputs. Although a large number of transcripts are affected by the circadian oscillator, very little is known about their regulation and function. We show here that the Drosophila takeout gene, one of the output genes of the circadian oscillator, is regulated similarly to the circadian clock genes Clock (Clk) and cry. takeout RNA levels are at constant high levels in Clk JRK mutants. The circadian transcription factor PAR domain protein 1 (Pdp1ε) is a transcription factor that had previously been postulated to control clock output genes, particularly genes regulated similarly to Clk. In agreement with this, we show here that Pdp1ε is a regulator of takeout. Takeout levels are low in flies with reduced Pdp1ε and high in flies with increased amounts of Pdp1ε. Furthermore, flies with reduced or elevated Pdp1ε levels in the fat body display courtship defects, identifying Pdp1ε as an important transcriptional regulator in that tissue.fat body | courtship | clock | Drosophila G enetic and molecular analyses have yielded significant insight into the genes that constitute the core components of the Drosophila circadian clock (reviewed in refs. 1-3). It is regulated by two interlocked transcription/translation-based feedback loops, the period/timeless (per/tim) and Clock (Clk) loops (4). In addition, the regulation of the nuclear entry of proteins, their degradation rate, and phosphorylation state are crucial regulatory steps that are controlled by and contribute to the circadian clock. The per/tim cycle starts with the binding of CLK/CYC heterodimers to E-box promoter elements of the per and tim genes and their subsequent transcriptional activation. Eventually, the newly formed PER and TIM proteins will enter the nucleus and inhibit CLK/CYC action, thereby inhibiting the transcription of their own genes (5-7). Transcription of per and tim will resume once their protein levels have decreased sufficiently to release the inhibition of CLK/CYC. Rhythmic expression of Clock mRNA is regulated in the second loop, the Clock loop. CLK/CYC activate vrille (vri) and Pdp1ε, a transcriptional repressor and activator respectively, that have been shown to bind the Clock promoter competitively (8, 9). Although it was thought that this competition accounts for the oscillatory regulation of Clk mRNA, the fact that Clk mRNA levels are still high in Clk JRK mutants (4) and that the core oscillator is only minimally impacted in flies with increased or decreased PAR domain protein 1 (Pdp1ε) levels (depending on the allele/transgene and tissue examined) (10-12), indicate that an as yet unknown activator is required for Clk transcription. It has recently been demonstrated that CLK protein levels are constant in cells and that it is the phosphorylation state of the protein that determines its binding to DNA and its transcriptional activator function (7).Although locomotor activity is the best-characterized circadian output, the circadian clock regulates numerous other outputs such as sleep (13-16), n...

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“…These criteria are used to study sleep at early developmental ages before the onset of differentiated EEG [11] and in genetically tractable organisms such as fruit flies, zebra fish and even nematodes [12][13][14][15][16][17][18]. (For discussion on whether electrographic and behaviorally defined sleep represent the same phenomena, please see: [10,19]).…”

Section: Typical Posturementioning

confidence: 99%

“…The greatest strides in the molecular dissection of sleep have been made in the fruit fly [18]. Using random mutagenesis, Cirelli et al screened more than 6000 lines of flies for short sleep length [60].…”

Section: Genetic Exceptionsmentioning

confidence: 99%

“…In Drosophila shaker channels are expressed mostly in the mushroom bodies and neuropil of the brain [60]; a brain area largely responsible for sleep cycles in drosophila [18]. The mouse equivalent of the shaker gene, Kcna, codes for Kv1.2, a shaker-like voltage-dependent potassium channel that is highly expressed in the thalamocortical system [61].…”

Section: Drosophila and Micementioning

confidence: 99%

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Is Sleep Beyond Our Control?

Þorsteinsson¹,

Karlsson²

2009

TOSLPJ

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Sleep is mysterious. It is ubiquitous and vital, yet its function remains unknown. There are, however, exceptions from the omnipresence of sleep: Birds that exhibit less sleep drive during migration; cetaceans and dolphins that sidestep the need for sleep by sleeping with one hemisphere at a time; frogs that do not seem to sleep at all; and strains of mice and fruit flies that sleep less than their wild-type counterparts. Moreover, new drugs have been discovered that combat the need for sleep in humans without the well known side effects of common stimulants. In the current review, the different ways of evading sleep will be examined. It will be argued that to understand how sleep can be controlled research efforts need to be extended to non-standard laboratory animals that exhibit different methods of evading sleep. Finally, it is argued that emerging clues point to increased membrane excitability as the common neural process used to execute seemingly different forms of sleep-evasion.

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Molecular Analysis of Sleep: Wake Cycles inDrosophila

Cited by 29 publications

References 47 publications

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

The circadian output gene takeout is regulated by Pdp1ε

Is Sleep Beyond Our Control?

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