Inter-organ Wingless/Ror/Akt signaling regulates nutrient-dependent hyperarborization of somatosensory neurons
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Evaluation Summary:
Nutrition profoundly affects neural development. The Uemura lab previously reported that C4da neurons elaborate complex dendrites when larvae grow on low-yeast diets, a phenomenon called neural sparing. In this current study, they define the molecular mechanism underlying the nutrition-mediated phenomenon and identify that the inter-organ Wingless/Ror/Akt pathway between the neuron and its adjacent muscles is necessary and sufficient to mediate dendrite overbranching in the low-yeast condition.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)
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Abstract
Nutrition in early life has profound effects on an organism, altering processes such as organogenesis. However, little is known about how specific nutrients affect neuronal development. Dendrites of class IV dendritic arborization neurons in Drosophila larvae become more complex when the larvae are reared on a low-yeast diet compared to a high-yeast diet. Our systematic search for key nutrients revealed that the neurons increase their dendritic terminal densities in response to a combined deficiency in vitamins, metal ions, and cholesterol. The deficiency of these nutrients upregulates Wingless in a closely located tissue, body wall muscle. Muscle-derived Wingless activates Akt in the neurons through the receptor tyrosine kinase Ror, which promotes the dendrite branching. In larval muscles, the expression of wingless is regulated not only in this key nutrient-dependent manner, but also by the JAK/STAT signaling pathway. Additionally, the low-yeast diet blunts neuronal light responsiveness and light avoidance behavior, which may help larvae optimize their survival strategies under low-nutritional conditions. Together, our studies illustrate how the availability of specific nutrients affects neuronal development through inter-organ signaling.
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Evaluation Summary:
Nutrition profoundly affects neural development. The Uemura lab previously reported that C4da neurons elaborate complex dendrites when larvae grow on low-yeast diets, a phenomenon called neural sparing. In this current study, they define the molecular mechanism underlying the nutrition-mediated phenomenon and identify that the inter-organ Wingless/Ror/Akt pathway between the neuron and its adjacent muscles is necessary and sufficient to mediate dendrite overbranching in the low-yeast condition.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
The Uemura lab previously reported that C4da neurons elaborate complex dendrites when larvae grow on low-yeast diets, a phenomenon called neural sparing. In the present study, they elegantly define that the inter-organ Wingless/Ror/Akt pathway between the neuron and its adjacent muscles is necessary and sufficient to mediate dendrite over branching in the low-yeast condition. This study provides a mechanistic explanation of how the dendrite hyperarborization is caused by the crosstalk among fat body, muscle, and sensory neurons. It is likely a general mechanism and phenomenon across species.
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Reviewer #2 (Public Review):
The manuscript by Kanaoka et al addresses their former discovery (Watanabe et al., 2017) on how Drosophila larvae feeding on a low yeast diet without sufficient nutrition would promote dendritic hyperarborization of the somatosensory neurons. They first showed that metal ions, vitamins, and cholesterol are the major components missing in the low yeast diet and could suppress hyperarborization when they are supplemented in the low yeast diet. Through genetic assays, they showed that Akt/TOR signaling is involved. Since the TOR pathway has been described previously by (Poe et al, 2020), they took a different direction to screen involved upstream receptor tyrosine kinases and showed that Ror is required in neurons for hyperarborization. Since Ror and the co-receptor Fz which was also shown to be involved in …
Reviewer #2 (Public Review):
The manuscript by Kanaoka et al addresses their former discovery (Watanabe et al., 2017) on how Drosophila larvae feeding on a low yeast diet without sufficient nutrition would promote dendritic hyperarborization of the somatosensory neurons. They first showed that metal ions, vitamins, and cholesterol are the major components missing in the low yeast diet and could suppress hyperarborization when they are supplemented in the low yeast diet. Through genetic assays, they showed that Akt/TOR signaling is involved. Since the TOR pathway has been described previously by (Poe et al, 2020), they took a different direction to screen involved upstream receptor tyrosine kinases and showed that Ror is required in neurons for hyperarborization. Since Ror and the co-receptor Fz which was also shown to be involved in receiving Wg signals, they found that Wg secreted from nearby muscle cells is required in the process. Significantly, Wg was unregulated at the transcriptional level in muscle cells of larvae feeding on a low yeast diet. They further suggest that Wg expression is derepressed by the down-regulation of the Jak/STAT signaling activity in muscle cells, and the Jak/STAT signaling activity depends on the cytokine Upd2 secreted from the fat body that responds to the nutritional status. Finally, from electrophysiological and behavior studies, they suggest that larvae feeding on a low yeast diet seem less responsive to strong blue light, allowing larvae to forage even under noxious stimulations.
The major strength of the study is the identification of the muscle-derived Wg signals to promote dendrite hyperarborization. The induction of Wg expression by a low yeast diet and the requirement of Wg to induce hyperarborization are key results to strongly support the conclusion. Also, the analyses of the Wg co-receptor Ror/Fz that are required in neurons for the same process and the elevation of pAkt further strengthen the involvement of Wg signaling. In a previous study by Poe et al, eLife (2020), they showed the involvement of the FoxO/TOR pathway in inducing autophagy in the dendrite-innervated epidermal cells. Thus, multiple organs/tissues seem to respond to a low yeast diet and together promote dendrite growth.
One weakness in the study is the inconsistency in the genetic analysis of the involvement of the Dome/Jak/Stat pathway in Wg regulation. While the idea is to link this pathway to the fat body secreted ligand Upd2 which is known to be one primary target regulated by nutrition/food intake.
The authors have developed an AI-assisted D-term for semi-automatic analysis of dendritic parameters, and the quantification of the dendritic field sizes vs branch terminal numbers in a two-dimensional axis is useful to the community.
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Reviewer #3 (Public Review):
The finding that wg is regulated in muscle by diet and that a wnt signaling pathway in neurons is involved in diet-induced branching is intriguing. However, the link between these players and Akt is quite tenuous, and not convincing. In order to build on the nice finding that wg from muscle impacts neuron branching through Ror, it will be critical to analyze the downstream components of the pathway more critically.
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