Biology subjects

Nagoshi, E.

Publications and source records attributed to Nagoshi, E..

3 recordsLinked to original sources

bioRxiv2020

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

Various 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.

neuroscience↗

bioRxiv2020

Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor

The degeneration of dopaminergic (DA) neurons in the substantia nigra is a hallmark of Parkinsons disease (PD). Dysregulation of developmental transcription factors is implicated in dopaminergic neurodegeneration, but the underlying molecular mechanisms remain largely unknown. Drosophila Fer2 is a prime example of a developmental transcription factor required for the birth and maintenance of midbrain DA neurons. Using an approach combining ChIP-seq, RNA-seq, and genetic epistasis experiments with PD-linked genes, here we demonstrate that Fer2 controls a transcriptional network to maintain mitochondrial structure and function, and thus confers dopaminergic neuroprotection against genetic and oxidative insults. We further show that conditional ablation of Nato3, a mouse homolog of Fer2, in differentiated DA neurons results in locomotor impairments and mitochondrial abnormality in aged mice. Our results reveal the essential and conserved role of Fer2 homologs in the mitochondrial maintenance of midbrain DA neurons, opening new perspectives for modelling and treating PD.

neuroscience↗

bioRxiv2019

Nitric Oxide Mediates Neuro-Glial Interaction that Shapes Drosophila Circadian Behavior

Drosophila circadian behavior relies on the network of heterogeneous groups of clock neurons. Short -and long-range signaling within the pacemaker circuit coordinates molecular and neural rhythms of clock neurons to generate coherent behavioral output. The neurochemistry of circadian behavior is complex and remains incompletely understood. Here we demonstrate that the gaseous messenger nitric oxide (NO) is a signaling molecule linking circadian pacemaker to rhythmic locomotor activity. We show that two independent mutants lacking nitric oxide synthase (NOS) have severely disturbed locomotor behavior both in light-dark cycles and constant darkness, although molecular clocks in the main pacemaker neurons are unaffected. Behavioral phenotypes are due in part to the malformation of neurites of the main pacemaker neurons, s-LNvs. Using cell-type selective and stage-specific gain -and loss-of-function of NOS, we demonstrate that NO secreted from diverse cellular clusters non-cell-autonomously affect molecular and behavioral rhythms. We further identify glia as a major source of NO that regulates circadian locomotor output. These results reveal for the first time the critical role of NO signaling in the Drosophila circadian system and highlight the importance of neuro-glial interaction in the neural circuit output.\n\nAuthor summaryCircadian rhythms are daily cycles of physiological and behavioral processes found in most plants and animals on our planet from cyanobacteria to humans. Circadian rhythms allow organisms to anticipate routine daily and annual changes of environmental conditions and efficiently adapt to them. Fruit fly Drosophila melanogaster is an excellent model to study this phenomenon, as its versatile toolkit enables the study of genetic, molecular and neuronal mechanisms of rhythm generation. Here we report for the first time that gasotransmitter nitric oxide (NO) has a broad, multi-faceted impact on Drosophila circadian rhythms, which takes place both during the development and the adulthood. We also show that one of the important contributors of NO to circadian rhythms are glial cells. The second finding highlights that circadian rhythms of higher organisms are not simply controlled by the small number of pacemaker neurons but are generated by the system that consists of many different players, including glia.

neuroscience↗