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Anaplastic Lymphoma Kinase Acts in the Drosophila Mushroom Body to Negatively Regulate Sleep.

Bai L, Sehgal A - PLoS Genet. (2015)

Bottom Line: We show that Alk mutants have increased sleep.We also report that mutations in Nf1 produce a sexually dimorphic short sleep phenotype, and suppress the long sleep phenotype of Alk.Thus Alk and Nf1 interact in both learning and sleep regulation, highlighting a common pathway in these two processes.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Though evidence is mounting that a major function of sleep is to maintain brain plasticity and consolidate memory, little is known about the molecular pathways by which learning and sleep processes intercept. Anaplastic lymphoma kinase (Alk), the gene encoding a tyrosine receptor kinase whose inadvertent activation is the cause of many cancers, is implicated in synapse formation and cognitive functions. In particular, Alk genetically interacts with Neurofibromatosis 1 (Nf1) to regulate growth and associative learning in flies. We show that Alk mutants have increased sleep. Using a targeted RNAi screen we localized the negative effects of Alk on sleep to the mushroom body, a structure important for both sleep and memory. We also report that mutations in Nf1 produce a sexually dimorphic short sleep phenotype, and suppress the long sleep phenotype of Alk. Thus Alk and Nf1 interact in both learning and sleep regulation, highlighting a common pathway in these two processes.

No MeSH data available.


Related in: MedlinePlus

Alk does not interact with Nf1 to control circadian rhythms.Representative activity graphs for each genotype are shown with activity double-plotted (2 day/night cycles). Gray and black bars at the top indicate subjective days and nights. Flies were raised and entrained at 18°C, monitored for 4 days in constant darkness at 18°C and then at 29°C for 4 days. Upon the temperature shift, iso31 and Alkts/1 flies manifest a phase shift in their activity rhythms. Nf1P1/P2 and Alkts/1;Nf1P1/P2 double mutants are arrhythmic.
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pgen.1005611.g008: Alk does not interact with Nf1 to control circadian rhythms.Representative activity graphs for each genotype are shown with activity double-plotted (2 day/night cycles). Gray and black bars at the top indicate subjective days and nights. Flies were raised and entrained at 18°C, monitored for 4 days in constant darkness at 18°C and then at 29°C for 4 days. Upon the temperature shift, iso31 and Alkts/1 flies manifest a phase shift in their activity rhythms. Nf1P1/P2 and Alkts/1;Nf1P1/P2 double mutants are arrhythmic.

Mentions: Nf1 is part of the circadian output pathway that controls rest: activity rhythms [22]. As Alk was found to interact with Nf1 in sleep regulation, as well as in growth and learning, we asked whether Alk is required also for circadian rhythms and whether Alk and Nf1 interact in circadian pathways. We found that Alkts/1 trans-heterozygotes raised at 18°C maintained locomotor activity rhythms at the restrictive temperature of 29°C in constant darkness (Fig 8 and Table 1), indicating Alk is not required to maintain circadian activity. Indeed, the FFT values, a measure of rhythm strength, of Alkts/1 and Alkts/Def flies were higher at 29°C than at 18°C, suggesting that loss of Alk may actually improve rhythms rather than disrupt them. However, inhibiting Alk failed to rescue the circadian defects in Nf1 flies: Alkts/1; Nf1P1/P2 double mutant were arrhythmic, just like Nf1 single mutants. To exclude a requirement for Alk in the development of circadian circuits, we also tested Alkts homozygous flies raised at 25°C, at which temperature Alkts flies have moderate lethality [19]. The partial reduction in ALK function throughout development did not cause arrhythmia nor did it suppress arrhythmia in Nf1P1/P2 flies (Table 1). These results suggest that Alk does not function in the circadian output circuit regulated by Nf1.


Anaplastic Lymphoma Kinase Acts in the Drosophila Mushroom Body to Negatively Regulate Sleep.

Bai L, Sehgal A - PLoS Genet. (2015)

Alk does not interact with Nf1 to control circadian rhythms.Representative activity graphs for each genotype are shown with activity double-plotted (2 day/night cycles). Gray and black bars at the top indicate subjective days and nights. Flies were raised and entrained at 18°C, monitored for 4 days in constant darkness at 18°C and then at 29°C for 4 days. Upon the temperature shift, iso31 and Alkts/1 flies manifest a phase shift in their activity rhythms. Nf1P1/P2 and Alkts/1;Nf1P1/P2 double mutants are arrhythmic.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4633181&req=5

pgen.1005611.g008: Alk does not interact with Nf1 to control circadian rhythms.Representative activity graphs for each genotype are shown with activity double-plotted (2 day/night cycles). Gray and black bars at the top indicate subjective days and nights. Flies were raised and entrained at 18°C, monitored for 4 days in constant darkness at 18°C and then at 29°C for 4 days. Upon the temperature shift, iso31 and Alkts/1 flies manifest a phase shift in their activity rhythms. Nf1P1/P2 and Alkts/1;Nf1P1/P2 double mutants are arrhythmic.
Mentions: Nf1 is part of the circadian output pathway that controls rest: activity rhythms [22]. As Alk was found to interact with Nf1 in sleep regulation, as well as in growth and learning, we asked whether Alk is required also for circadian rhythms and whether Alk and Nf1 interact in circadian pathways. We found that Alkts/1 trans-heterozygotes raised at 18°C maintained locomotor activity rhythms at the restrictive temperature of 29°C in constant darkness (Fig 8 and Table 1), indicating Alk is not required to maintain circadian activity. Indeed, the FFT values, a measure of rhythm strength, of Alkts/1 and Alkts/Def flies were higher at 29°C than at 18°C, suggesting that loss of Alk may actually improve rhythms rather than disrupt them. However, inhibiting Alk failed to rescue the circadian defects in Nf1 flies: Alkts/1; Nf1P1/P2 double mutant were arrhythmic, just like Nf1 single mutants. To exclude a requirement for Alk in the development of circadian circuits, we also tested Alkts homozygous flies raised at 25°C, at which temperature Alkts flies have moderate lethality [19]. The partial reduction in ALK function throughout development did not cause arrhythmia nor did it suppress arrhythmia in Nf1P1/P2 flies (Table 1). These results suggest that Alk does not function in the circadian output circuit regulated by Nf1.

Bottom Line: We show that Alk mutants have increased sleep.We also report that mutations in Nf1 produce a sexually dimorphic short sleep phenotype, and suppress the long sleep phenotype of Alk.Thus Alk and Nf1 interact in both learning and sleep regulation, highlighting a common pathway in these two processes.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Though evidence is mounting that a major function of sleep is to maintain brain plasticity and consolidate memory, little is known about the molecular pathways by which learning and sleep processes intercept. Anaplastic lymphoma kinase (Alk), the gene encoding a tyrosine receptor kinase whose inadvertent activation is the cause of many cancers, is implicated in synapse formation and cognitive functions. In particular, Alk genetically interacts with Neurofibromatosis 1 (Nf1) to regulate growth and associative learning in flies. We show that Alk mutants have increased sleep. Using a targeted RNAi screen we localized the negative effects of Alk on sleep to the mushroom body, a structure important for both sleep and memory. We also report that mutations in Nf1 produce a sexually dimorphic short sleep phenotype, and suppress the long sleep phenotype of Alk. Thus Alk and Nf1 interact in both learning and sleep regulation, highlighting a common pathway in these two processes.

No MeSH data available.


Related in: MedlinePlus