Evolutionarily conserved regulation of sleep by epidermal growth factor receptor signaling

Lee, Dan A.; Liu, Justin; Hong, Young; Lane, Jacqueline M.; Hill, Andrew J.; Hou, Sarah; Wang, Heming; Oikonomou, Grigorios; Pham, Uyen; Engle, Jae; Saxena, Richa; Prober, David A.

doi:10.1126/sciadv.aax4249

Cited by 31 publications

(43 citation statements)

References 70 publications

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“…Third, colocalization analyses refined genetic effects previously described at the 198 KSR2 locus implicated in ERK/EGFR signaling 23 , a pathway with an established causal role in sleep regulation in C. elegans, Drosophila, and zebrafish 33,34 . This included an 200 intronic variant in KSR2, a gene that encodes a scaffold protein for ERK cascade signaling 35 Fifth, we found evidence of association for variants in PRRC2C, one of three 210 orthologs of the Drosophila nocte gene 36 .…”

Section: Napping Genetic Variants Share Causal Variants With Other Slmentioning

confidence: 71%

Genetic determinants of daytime napping and effects on cardiometabolic health

Dashti

Daghlas

Lane

et al. 2020

Preprint

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Daytime napping is a common, heritable behavior, but its genetic basis and causal relationship with cardiometabolic health remains unclear. Here, we performed a genome-wide association study of self-reported daytime napping in the UK Biobank (n=452,633) and identified 123 loci of which 60 replicated in 23andMe research participants (n=541,333). Findings included missense variants in established drug targets (HCRTR1, HCRTR2), genes with roles in arousal (TRPC6, PNOC), and genes suggesting an obesity-hypersomnolence pathway (PNOC, PATJ). Signals were concordant with accelerometer-measured daytime inactivity duration and 33 signals colocalized with signals for other sleep phenotypes. Cluster analysis identified 3 clusters suggesting distinct nap-promoting mechanisms with heterogeneous associations with cardiometabolic outcomes. Mendelian randomization showed potential causal links between more frequent daytime napping and higher systolic blood pressure, diastolic blood pressure, and waist circumference.

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Section: Napping Genetic Variants Share Causal Variants With Other Slmentioning

confidence: 71%

Genetic determinants of daytime napping and effects on cardiometabolic health

Dashti

Daghlas

Lane

et al. 2020

Preprint

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“…To verify that this stimulation paradigm indeed results in stimulation of NPVF neurons, we first tested Tg(npvf:ReaChR-mCitrine) ; Tg(npvf:GCaMP6s-tdTomato) animals (Lee et al, 2017; Lee et al, 2019). We first recorded baseline GCaMP6s fluorescence in npvf -expressing neurons, then optogenetically stimulated these neurons, and then recorded post-stimulation GCaMP6s fluorescence in these neurons ( Figure 2 – figure supplement 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…The hypothalamic-hindbrain neuronal circuit that we have described can be integrated into a larger sleep-promoting network. We recently reported that epidermal growth factor receptor (EGFR) signaling is necessary and sufficient for normal sleep amounts in zebrafish, and that it promotes sleep, in part, via the NPVF system (Lee et al, 2019). We found that it does so by both promoting the expression of npvf and by stimulating npvf -expressing neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, pharmacological inhibition or mutation of extracellular regulated kinase (ERK), which mediates EGFR signaling, was shown to result in reduced sleep in mice (Mikhail et al, 2017). The spatial expression of NPVF neurons within the hypothalamus is highly conserved between humans, rodents, and zebrafish (Lee et al, 2017; Liu et al, 2001; Ubuka et al, 2009; Yelin-Bekerman et al, 2015), as are the expression of EGFR and its ligands in zebrafish and rodent brains (Lee et al, 2019; Ma et al, 1994; Ma et al, 1992). However, NPVF has not been studied in the context of mammalian sleep, so further studies are required to determine whether the EGFR/NPVF/RN circuit described in zebrafish is conserved in mammals.…”

Section: Discussionmentioning

confidence: 99%

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Neuropeptide VF neurons promote sleep via the serotonergic raphe

Lee

Oikonomou

Cammidge

et al. 2019

Preprint

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15Although several sleep-regulating neurons have been identified, little is known about how they 16 interact with each other for sleep/wake control. We previously identified neuropeptide VF (NPVF) 17 and the hypothalamic neurons that produce it as a sleep-promoting system (Lee et al., 2017). 18Here we use zebrafish to describe a neural circuit in which neuropeptide VF (npvf)-expressing 19 neurons control sleep via the serotonergic raphe nuclei (RN), a hindbrain structure that promotes 20 sleep in both diurnal zebrafish and nocturnal mice. Using genetic labeling and calcium imaging, 21we show that npvf-expressing neurons innervate and activate serotonergic RN neurons. We 22 additionally demonstrate that optogenetic stimulation of npvf-expressing neurons induces sleep 23 in a manner that requires NPVF and is abolished when the RN are ablated or lack serotonin. 24Finally, genetic epistasis demonstrates that NPVF acts upstream of serotonin in the RN to 25 maintain normal sleep levels. These findings reveal a novel hypothalamic-hindbrain circuit for 26 sleep/wake control. 28While several sleep-and wake-promoting neuronal populations have been identified (reviewed in 30 (Bringmann, 2018; Liu and Dan, 2019; Saper and Fuller, 2017; Scammell et al., 2017)), 31 characterizing and understanding the functional and hierarchical relationships between these 32 populations is essential for understanding how the brain regulates sleep and wake states 33 (Oikonomou and Prober, 2017). Recent evidence from zebrafish and mice demonstrate that the 34 serotonergic raphe nuclei (RN) are critical for the initiation and maintenance of sleep (Oikonomou 35 et al., 2019), in contrast with previous models suggesting a wake-promoting role for the RN that 36 were largely based on their wake-active nature (Saper and Fuller, 2017; Scammell et al., 2017; 37Weber and Dan, 2016). In zebrafish, mutation of tryptophan hydroxylase 2 (tph2), which is 38 required for serotonin (5-HT) synthesis in the RN, results in reduced sleep, sleep depth, and 39 homeostatic response to sleep deprivation (Oikonomou et al., 2019). Pharmacological inhibition 40 of 5-HT synthesis or ablation of the RN also results in reduced sleep. Consistent with a sleep-41 promoting role for the raphe, optogenetic stimulation of raphe neurons results in increased sleep.42 Similarly, in mice, ablation of the RN results in increased wakefulness and an impaired 43 homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation of the RN at a 44 rate similar to their baseline pattern of activity induces NREM sleep. These complementary results 45 in zebrafish and mice (Oikonomou et al., 2019), along with classical ablation and pharmacological 46 studies (Ursin, 2008), indicate an evolutionarily conserved role for the serotonergic system in 47 promoting vertebrate sleep. However, it is unclear how the RN are themselves regulated to 48 promote sleep. 50Trans-synaptic retrograde viral tracing studies have identified substantial inputs to the RN from 51 hypothalamic ...

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“…Other possible Pum functions that could have played a role in our results include EGFR and the regulation of inflammatory pathways. EGFR is a direct target of Pum in Drosophila and has been implicated in sleep regulation in flies, worms, zebrafish and humans (Foltenyi et al, 2007;Kim et al, 2012;Lee et al, 2019;Konietzka et al, 2020). These studies showed that EGFR signaling promotes sleep in all organisms tested but its role in sleep homeostasis was only examined in zebrafish.…”

Section: Discussionmentioning

confidence: 99%

Pumilio Regulates Sleep Homeostasis in Response to Chronic Sleep Deprivation in Drosophila melanogaster

et al. 2020

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Recent studies have identified the Drosophila brain circuits involved in the sleep/wake switch and have pointed to the modulation of neuronal excitability as one of the underlying mechanisms triggering sleep need. In this study we aimed to explore the link between the homeostatic regulation of neuronal excitability and sleep behavior in the circadian circuit. For this purpose, we selected Pumilio (Pum), whose main function is to repress protein translation and has been linked to modulation of neuronal excitability during chronic patterns of altered neuronal activity. Here we explore the effects of Pum on sleep homeostasis in Drosophila melanogaster, which shares most of the major features of mammalian sleep homeostasis. Our evidence indicates that Pum is necessary for sleep rebound and that its effect is more pronounced during chronic sleep deprivation (84 h) than acute deprivation (12 h). Knockdown of pum, results in a reduction of sleep rebound during acute sleep deprivation and the complete abolishment of sleep rebound during chronic sleep deprivation. Based on these findings, we propose that Pum is a critical regulator of sleep homeostasis through neural adaptations triggered during sleep deprivation.

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Evolutionarily conserved regulation of sleep by epidermal growth factor receptor signaling

Cited by 31 publications

References 70 publications

Genetic determinants of daytime napping and effects on cardiometabolic health

Genetic determinants of daytime napping and effects on cardiometabolic health

Neuropeptide VF neurons promote sleep via the serotonergic raphe

Pumilio Regulates Sleep Homeostasis in Response to Chronic Sleep Deprivation in Drosophila melanogaster

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