Neurofibromin 1 in mushroom body neurons mediates circadian wake drive through activating cAMP–PKA signaling

AbstractVarious behavioral and cognitive states exhibit circadian variations in animals across phyla including Drosophila melanogaster, in which only ~0.1% of the brain’s neurons contain circadian clocks. Clock neurons transmit the timing information to a plethora of non-clock neurons via poorly understood mechanisms. Here, we address the molecular underpinning of this phenomenon by profiling circadian gene expression in non-clock neurons that constitute the mushroom body, the center of associative learning and sleep regulation. We show that circadian clocks drive rhythmic expression of hundreds of genes in mushroom body neurons, including the Neurofibromin 1 (Nf1) tumor suppressor gene and Pka-C1. Circadian clocks also drive calcium rhythms in mushroom body neurons via NF1-cAMP/PKA-C1 signaling, eliciting higher mushroom body activity during the day than at night, thereby promoting daytime wakefulness. These findings reveal the pervasive, non-cell-autonomous circadian regulation of gene expression in the brain and its role in sleep.

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Rhythmic expression of Neurofibromin 1 in mushroom body neurons mediates circadian wake drive through activating cAMP−PKA signaling

10.1101/2020.09.16.299859 ◽

2020 ◽

Author(s):

Pedro Machado Almeida ◽

Blanca Lago Solis ◽

Alexis Feidler ◽

Emi Nagoshi

Keyword(s):

Mushroom Body ◽

Regulation Of Gene Expression ◽

Neurofibromatosis Type ◽

Rna Seq ◽

Sleep Regulation ◽

Rhythmic Expression ◽

Cognitive States ◽

Neurofibromin 1 ◽

The Brain

SUMMARYVarious behavioral and cognitive states exhibit circadian variations in animals across phyla including Drosophila, in which only ∼0.1% of the entire brain neurons contain circadian clocks. This suggests that clock neurons communicate with a plethora of non-clock neurons to transmit the timing information to gate various behavioral outputs in Drosophila. Here, we address the molecular underpinning of this phenomenon by performing circadian RNA-seq analysis of non-clock neurons that constitute the mushroom body (MB), the center of information processing and sleep regulation. We identify hundreds of genes rhythmically expressed in the MB, including the Drosophila ortholog of Neurofibromin 1 (Nf1), the gene responsible for neurofibromatosis type 1 (NF1). Rhythmic expression of Nf1 promotes daytime wakefulness by activating cAMP−PKA signaling and increasing excitability of the MB. These findings reveal the pervasive, non-cell-autonomous circadian regulation of gene expression in the brain and its role in sleep, with implications in the pathology of NF1.

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Computational modelling unravels the precise clockwork of cyanobacteria

Interface Focus ◽

10.1098/rsfs.2018.0038 ◽

2018 ◽

Vol 8 (6) ◽

pp. 20180038 ◽

Cited By ~ 4

Author(s):

Nicolas M. Schmelling ◽

Ilka M. Axmann

Keyword(s):

Gene Expression ◽

Gene Regulation ◽

Circadian Clock ◽

Environmental Changes ◽

Regulation Of Gene Expression ◽

Computational Modelling ◽

Circadian Clocks ◽

Fitness Advantage ◽

Fundamental Part ◽

Global Gene Regulation

Precisely timing the regulation of gene expression by anticipating recurring environmental changes is a fundamental part of global gene regulation. Circadian clocks are one form of this regulation, which is found in both eukaryotes and prokaryotes, providing a fitness advantage for these organisms. Whereas many different eukaryotic groups harbour circadian clocks, cyanobacteria are the only known oxygenic phototrophic prokaryotes to regulate large parts of their genes in a circadian fashion. A decade of intensive research on the mechanisms and functionality using computational and mathematical approaches in addition to the detailed biochemical and biophysical understanding make this the best understood circadian clock. Here, we summarize the findings and insights into various parts of the cyanobacterial circadian clock made by mathematical modelling. These findings have implications for eukaryotic circadian research as well as synthetic biology harnessing the power and efficiency of global gene regulation.

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Relationships between circadian rhythms and modulation of gene expression by glucocorticoids in skeletal muscle

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90399.2008 ◽

2008 ◽

Vol 295 (4) ◽

pp. R1031-R1047 ◽

Cited By ~ 46

Author(s):

Richard R. Almon ◽

Eric Yang ◽

William Lai ◽

Ioannis P. Androulakis ◽

Svetlana Ghimbovschi ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Transcription Factors ◽

Circadian Rhythms ◽

Expression Patterns ◽

Regulation Of Gene Expression ◽

Biological Rhythms ◽

Peripheral Tissues ◽

Rhythmic Expression ◽

Gastrocnemius Muscles

The existence and maintenance of biological rhythms linked to the 24-h light-dark cycle are essential to the health and functioning of an organism. Although much is known concerning central clock mechanisms, much less is known about control in peripheral tissues. In this study, circadian regulation of gene expression was examined in rat skeletal muscle. A rich time series involving 54 animals euthanized at 18 distinct time points within the 24-h cycle was performed, and mRNA expression in gastrocnemius muscles was examined using Affymetrix gene arrays. Data mining identified 109 genes that were expressed rhythmically, which could be grouped into eight distinct temporal clusters within the 24-h cycle. These genes were placed into 11 functional categories, which were examined within the context of temporal expression. Transcription factors involved in the regulation of central rhythms were examined, and eight were found to be rhythmically expressed in muscle. Because endogenous glucocorticoids are a major effector of circadian rhythms, genes identified here were compared with those identified in previous studies as glucocorticoid regulated. Of the 109 genes identified here as circadian rhythm regulated, only 55 were also glucocorticoid regulated. Examination of transcription factors involved in circadian control suggests that corticosterone may be the initiator of their rhythmic expression patterns in skeletal muscle.

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Linking transcription, RNA polymerase II elongation and alternative splicing

Biochemical Journal ◽

10.1042/bcj20200475 ◽

2020 ◽

Vol 477 (16) ◽

pp. 3091-3104 ◽

Cited By ~ 1

Author(s):

Luciana E. Giono ◽

Alberto R. Kornblihtt

Keyword(s):

Gene Expression ◽

Alternative Splicing ◽

Rna Polymerase Ii ◽

Environmental Changes ◽

Transcription Elongation ◽

Single Gene ◽

Regulation Of Gene Expression ◽

Regulation Of Transcription ◽

Stepping Stones ◽

Eukaryotic Transcription

Gene expression is an intricately regulated process that is at the basis of cell differentiation, the maintenance of cell identity and the cellular responses to environmental changes. Alternative splicing, the process by which multiple functionally distinct transcripts are generated from a single gene, is one of the main mechanisms that contribute to expand the coding capacity of genomes and help explain the level of complexity achieved by higher organisms. Eukaryotic transcription is subject to multiple layers of regulation both intrinsic — such as promoter structure — and dynamic, allowing the cell to respond to internal and external signals. Similarly, alternative splicing choices are affected by all of these aspects, mainly through the regulation of transcription elongation, making it a regulatory knob on a par with the regulation of gene expression levels. This review aims to recapitulate some of the history and stepping-stones that led to the paradigms held today about transcription and splicing regulation, with major focus on transcription elongation and its effect on alternative splicing.

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