Belly roll, a GPI-anchored Ly6 protein, regulates Drosophila melanogaster escape behaviors by modulating the excitability of nociceptive peptidergic interneurons
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eLife assessment
The study presents valuable findings on a gene called bero that affects the way larval Drosophila respond to nociceptive stimuli. This discovery is followed-up by the identification of neurons in which bero function is relevant for the modulation of nociceptive behavior, and by the additional identification of likely signaling molecules for conferring such modulation. The work will be of interest to neurobiologists working on genes, neural circuits, and behavior. While both interesting and methodologically elegant and diverse, important genetic controls for leaky expression of transgenes seem to be missing, as are alternative scenarios for results that, as the authors acknowledge, are unexpected or seemingly contradictory.
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Abstract
Appropriate modulation of escape behaviors in response to potentially damaging stimuli is essential for survival. Although nociceptive circuitry has been studied, it is poorly understood how genetic contexts affect relevant escape responses. Using an unbiased genome-wide association analysis, we identified an Ly6/α-neurotoxin family protein, Belly roll (Bero), which negatively regulates Drosophila nociceptive escape behavior. We show that Bero is expressed in abdominal leucokinin-producing neurons (ABLK neurons) and bero knockdown in ABLK neurons resulted in enhanced escape behavior. Furthermore, we demonstrated that ABLK neurons responded to activation of nociceptors and initiated the behavior. Notably, bero knockdown reduced persistent neuronal activity and increased evoked nociceptive responses in ABLK neurons. Our findings reveal that Bero modulates an escape response by regulating distinct neuronal activities in ABLK neurons.
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eLife assessment
The study presents valuable findings on a gene called bero that affects the way larval Drosophila respond to nociceptive stimuli. This discovery is followed-up by the identification of neurons in which bero function is relevant for the modulation of nociceptive behavior, and by the additional identification of likely signaling molecules for conferring such modulation. The work will be of interest to neurobiologists working on genes, neural circuits, and behavior. While both interesting and methodologically elegant and diverse, important genetic controls for leaky expression of transgenes seem to be missing, as are alternative scenarios for results that, as the authors acknowledge, are unexpected or seemingly contradictory.
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Reviewer #1 (Public Review):
This work identified a novel gene Belly roll (Bero) as a key protein that controls nociceptive escape behavior in Drosophila larvae using genome-wide association analysis. The authors show that constitutive deletion of Bero by CRISPR or RNAi knockdown of Bero expression shows enhanced escape rolling behavior induced by heat probe stimulation. They then showed that Bero is expressed specifically in dimm' pepti, Eh+, Ilp, and AbLK neurons. Next, they demonstrated that Bero RNAi knockdown specifically in ABLk neurons showed the mutant phenotype. Furthermore, they found that ABLK neurons exhibit spontaneous activity and, that Bero RNAi knockdown inhibited this spontaneous activity and increased the response latency to nociceptive stimulation in ABLK neurons.
Strong points of this study: Authors identify a novel …
Reviewer #1 (Public Review):
This work identified a novel gene Belly roll (Bero) as a key protein that controls nociceptive escape behavior in Drosophila larvae using genome-wide association analysis. The authors show that constitutive deletion of Bero by CRISPR or RNAi knockdown of Bero expression shows enhanced escape rolling behavior induced by heat probe stimulation. They then showed that Bero is expressed specifically in dimm' pepti, Eh+, Ilp, and AbLK neurons. Next, they demonstrated that Bero RNAi knockdown specifically in ABLk neurons showed the mutant phenotype. Furthermore, they found that ABLK neurons exhibit spontaneous activity and, that Bero RNAi knockdown inhibited this spontaneous activity and increased the response latency to nociceptive stimulation in ABLK neurons.
Strong points of this study: Authors identify a novel gene as a key protein that negatively controls nociceptive escape behavior in Drosophila. The data were presented clearly and the approach to identifying the gene was unique.
Weakness of this study:
I think if authors are able to link the variable bero expression levels in each GNP line and ABLK neural activity, the physiological function of Bero will be strong. I also appreciate the proposed model in the supplemental figure although it has not shown the evidence to link stress and Bero in this study. -
Reviewer #2 (Public Review):
Nociception is an essential sense to detect threats to bodily integrity, and nociceptive behavior is essential to deal with such threats adaptively to minimize actual harm. Intuitively, these processes might be regarded as hard-wired, and so the choice of topic of the present paper, namely the way nociceptive behavior can be MODULATED, is a strength. Also, a strength is the most elegant use of a wide range of suitable methods.
Weaknesses are a lack of proper genetic controls for leaky transgene expression in some of the experiments, and what appears to be an incomplete discussion of results that, as the authors acknowledge, are unexpected or seemingly contradictory.
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