Diverse paths for chemoreception in ciliated neurons contacting the cerebrospinal fluid in the spinal cord
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Curated by eLife
eLife Assessment
This study provides a useful anatomical resource by mapping the expression of four putative chemoreceptors in spinal cerebrospinal fluid-contacting neurons (CSF-cNs) of larval zebrafish. These descriptive findings offer an interesting entry point to explore how the nervous system senses signals within the spinal fluid microenvironment. The evidence supporting the spatial expression patterns of these receptors is convincing, utilizing high-resolution hybridization chain reaction (HCR) to validate previous transcriptomic data. However, the evidence remains incomplete regarding the actual functional roles of these receptors, as the study lacks protein-level validation, evidence of ligand availability in the CSF, or functional assays to demonstrate active chemoreception.
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Abstract
Cerebrospinal fluid-contacting neurons (CSF-cNs) are mechanosensory cells in the spinal cord that detect compression and regulate locomotion, posture, and morphogenesis. Although CSF-cNs respond to changes in pH, neurotransmitters and metabolites, their chemosensory repertoire is not fully understood. Using hybridization chain reaction, we investigated the distribution of expression of chemoreceptors in CSF-cNs and neighboring cells in the spinal cord. We found that CSF-cNs express receptors for glutamate (grm2), somatostatin (sstr2) and low-density lipoprotein (LDL) (ldlrad2), indicating roles in detecting glutamate, somatostatin and LDL in the CSF. High LDL receptor expression in CSF-contacting cells suggests CSF lipid capture. Most receptors were enriched but not exclusive to CSF-cNs and also appeared in ependymal radial glial cells. Our findings indicate multiple chemosensory pathways can sustain long-distance communication between neurons and glia through the cerebrospinal fluid.
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eLife Assessment
This study provides a useful anatomical resource by mapping the expression of four putative chemoreceptors in spinal cerebrospinal fluid-contacting neurons (CSF-cNs) of larval zebrafish. These descriptive findings offer an interesting entry point to explore how the nervous system senses signals within the spinal fluid microenvironment. The evidence supporting the spatial expression patterns of these receptors is convincing, utilizing high-resolution hybridization chain reaction (HCR) to validate previous transcriptomic data. However, the evidence remains incomplete regarding the actual functional roles of these receptors, as the study lacks protein-level validation, evidence of ligand availability in the CSF, or functional assays to demonstrate active chemoreception.
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Reviewer #1 (Public review):
Summary:
This manuscript examines the expression of putative chemoreceptors in CSF-contacting neurons of the larval zebrafish spinal cord. Using in situ hybridization, the authors show that sstr2a is preferentially expressed in ventral CSF-cNs, whereas grm2a, ptprna, and ldlrad2 are detected in both ventral and dorsolateral CSF-cNs, with additional expression in neighboring cells around the central canal.
Strengths:
The study provides useful anatomical information on the expression of putative chemoreceptors in CSF-contacting neurons. The experiments appear to be carefully performed, and the results are clearly presented with high-quality illustrations and informative schematics.
Weaknesses:
This work remains largely descriptive and based on mRNA expression. Therefore, the proposed roles in chemoreception, …
Reviewer #1 (Public review):
Summary:
This manuscript examines the expression of putative chemoreceptors in CSF-contacting neurons of the larval zebrafish spinal cord. Using in situ hybridization, the authors show that sstr2a is preferentially expressed in ventral CSF-cNs, whereas grm2a, ptprna, and ldlrad2 are detected in both ventral and dorsolateral CSF-cNs, with additional expression in neighboring cells around the central canal.
Strengths:
The study provides useful anatomical information on the expression of putative chemoreceptors in CSF-contacting neurons. The experiments appear to be carefully performed, and the results are clearly presented with high-quality illustrations and informative schematics.
Weaknesses:
This work remains largely descriptive and based on mRNA expression. Therefore, the proposed roles in chemoreception, ligand sensing, lipid capture, or long-range CSF signaling remain speculative without protein-level or functional validation.
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Reviewer #2 (Public review):
Summary:
Verran et al. leverage a previously published RNAseq dataset of zebrafish cerebrospinal fluid contacting neurons (CSF-cNs) to identify potential receptors involved in chemosensory signalling in these neurons. They then validate expression of the identified receptors by hybridization chain reaction (HCR) in zebrafish larvae. This way they uncover potential roles for the somatostatin receptor Sstr2a, metabotropic glutamtate receptor Grm2a, LDL receptor Ldlrad2 and the Phosphatase receptor Ptprna, suggesting the existence of numerous chemo-sensory pathways in CSF-cNs and providing a potential entry point for further investigation.
Strengths:
This is a useful resource; the provided HCR data that demonstrates expression of these receptors in CSF-cNs is convincing, and the finding that CSF-cNs express …
Reviewer #2 (Public review):
Summary:
Verran et al. leverage a previously published RNAseq dataset of zebrafish cerebrospinal fluid contacting neurons (CSF-cNs) to identify potential receptors involved in chemosensory signalling in these neurons. They then validate expression of the identified receptors by hybridization chain reaction (HCR) in zebrafish larvae. This way they uncover potential roles for the somatostatin receptor Sstr2a, metabotropic glutamtate receptor Grm2a, LDL receptor Ldlrad2 and the Phosphatase receptor Ptprna, suggesting the existence of numerous chemo-sensory pathways in CSF-cNs and providing a potential entry point for further investigation.
Strengths:
This is a useful resource; the provided HCR data that demonstrates expression of these receptors in CSF-cNs is convincing, and the finding that CSF-cNs express these receptors is interesting.
Weaknesses:
The overall insight provided by this manuscript is rather limited, essentially just demonstrating the expression of 4 receptors in CSF-cNs, whose expression was predicted to be enriched in these neurons anyway by a previously published dataset.
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Reviewer #3 (Public review):
Summary:
The authors aimed to identify new molecular pathways that could enable long-range signaling through the cerebrospinal fluid (CSF), focusing on a specialized class of neurons called CSF-contacting neurons (CSF-cNs) in larval zebrafish.
Strengths:
Anatomical validation of transcriptomic candidates using HCR, providing high-resolution spatial mapping of chemoreceptor expression in CSF-contacting neurons and neighboring spinal cord cells. The work broadens the potential understanding of CSF-cNs and offers a resource for future functional investigations of CSF-mediated signaling.
Weaknesses:
The principal limitation of the study is that the conclusions remain largely transcriptomic and inferential. Although HCR convincingly validates mRNA expression, no protein-level evidence is provided to demonstrate …
Reviewer #3 (Public review):
Summary:
The authors aimed to identify new molecular pathways that could enable long-range signaling through the cerebrospinal fluid (CSF), focusing on a specialized class of neurons called CSF-contacting neurons (CSF-cNs) in larval zebrafish.
Strengths:
Anatomical validation of transcriptomic candidates using HCR, providing high-resolution spatial mapping of chemoreceptor expression in CSF-contacting neurons and neighboring spinal cord cells. The work broadens the potential understanding of CSF-cNs and offers a resource for future functional investigations of CSF-mediated signaling.
Weaknesses:
The principal limitation of the study is that the conclusions remain largely transcriptomic and inferential. Although HCR convincingly validates mRNA expression, no protein-level evidence is provided to demonstrate receptor translation or subcellular localization, leaving uncertainty regarding functional receptor availability at the CSF interface. Moreover, the study does not establish whether the proposed ligands are present in the relevant CSF microenvironment or engage the identified receptors in vivo. As such, the functional significance of the proposed chemosensory pathways remains speculative.
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