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A Secreted Ig-Domain Protein Required in Both Astrocytes and Neurons for Regulation of Drosophila Night Sleep.

ABSTRACT: Endogenous rhythmic behaviors are evolutionarily conserved and essential for life. In mammalian and invertebrate models, well-characterized neuronal circuits and evolutionarily conserved mechanisms regulate circadian behavior and sleep [1-4]. In Drosophila, neuronal populations located in multiple brain regions mediate arousal, sleep drive, and homeostasis (reviewed in [3, 5-7]). Similar to mammals [8], there is also evidence that fly glial cells modulate the neuronal circuits controlling rhythmic behaviors, including sleep [1]. Here, we describe a novel gene (CG14141; aka Nkt) that is required for normal sleep. NKT is a 162-amino-acid protein with a single IgC2 immunoglobulin (Ig) domain and a high-quality signal peptide [9], and we show evidence that it is secreted, similar to its C. elegans ortholog (OIG-4) [10]. We demonstrate that Nkt-null flies or those with selective knockdown in either neurons or glia have decreased and fragmented night sleep, indicative of a non-redundant requirement in both cell types. We show that Nkt is required in fly astrocytes and in a specific set of wake-promoting neurons-the mushroom body (MB) ?'?' cells that link sleep to memory consolidation [11]. Importantly, Nkt gene expression is required in the adult nervous system for normal sleep, consistent with a physiological rather than developmental function for the Ig-domain protein.

SUBMITTER: Sengupta S

PROVIDER: S-EPMC6712560 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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A Secreted Ig-Domain Protein Required in Both Astrocytes and Neurons for Regulation of Drosophila Night Sleep.

Sengupta Sukanya S Crowe Lauren B LB You Samantha S Roberts Mary A MA Jackson F Rob FR

Current biology : CB 20190725 15

Endogenous rhythmic behaviors are evolutionarily conserved and essential for life. In mammalian and invertebrate models, well-characterized neuronal circuits and evolutionarily conserved mechanisms regulate circadian behavior and sleep [1-4]. In Drosophila, neuronal populations located in multiple brain regions mediate arousal, sleep drive, and homeostasis (reviewed in [3, 5-7]). Similar to mammals [8], there is also evidence that fly glial cells modulate the neuronal circuits controlling rhythm ...[more]

PMID: 31353186

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Project description:Secreted factors play a central role in normal and pathological processes in every tissue in the body. The brain is composed of a highly complex milieu of different cell types and few methods exist that can identify which individual cells in a complex mixture are secreting specific analytes. By identifying which cells are responsible, we can better understand neural physiology and pathophysiology, more readily identify the underlying pathways responsible for analyte production, and ultimately use this information to guide the development of novel therapeutic strategies that target the cell types of relevance. We present here a method for detecting analytes secreted from single human induced pluripotent stem cell (iPSC)-derived neural cells and have applied the method to measure amyloid ? (A?) and soluble amyloid precursor protein-alpha (sAPP?), analytes central to Alzheimer's disease pathogenesis. Through these studies, we have uncovered the dynamic range of secretion profiles of these analytes from single iPSC-derived neuronal and glial cells and have molecularly characterized subpopulations of these cells through immunostaining and gene expression analyses. In examining A? and sAPP? secretion from single cells, we were able to identify previously unappreciated complexities in the biology of APP cleavage that could not otherwise have been found by studying averaged responses over pools of cells. This technique can be readily adapted to the detection of other analytes secreted by neural cells, which would have the potential to open new perspectives into human CNS development and dysfunction.We have established a technology that, for the first time, detects secreted analytes from single human neurons and astrocytes. We examine secretion of the Alzheimer's disease-relevant factors amyloid ? (A?) and soluble amyloid precursor protein-alpha (sAPP?) and present novel findings that could not have been observed without a single-cell analytical platform. First, we identify a previously unappreciated subpopulation that secretes high levels of A? in the absence of detectable sAPP?. Further, we show that multiple cell types secrete high levels of A? and sAPP?, but cells expressing GABAergic neuronal markers are overrepresented. Finally, we show that astrocytes are competent to secrete high levels of A? and therefore may be a significant contributor to A? accumulation in the brain.

Dataset Information

A Secreted Ig-Domain Protein Required in Both Astrocytes and Neurons for Regulation of Drosophila Night Sleep.

Publications

A Secreted Ig-Domain Protein Required in Both Astrocytes and Neurons for Regulation of Drosophila Night Sleep.

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