Expression of immunoglobulin constant domain genes in neurons of the mouse central nervous system

In this study, Scheurer et al demonstrate that two genes encoding the effector domain of immunoglobulins are not only expressed by lymphocytes of the immune system but also by neurons in the central nervous system.

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Full guidelines are available on our Instructions for Authors page, https://www.life-sciencealliance.org/authors We encourage our authors to provide original source data, particularly uncropped/-processed electrophoretic blots and spreadsheets for the main figures of the manuscript. If you would like to add source data, we would welcome one PDF/Excel-file per figure for this information. These files will be linked online as supplementary "Source Data" files. ***IMPORTANT: It is Life Science Alliance policy that if requested, original data images must be made available. Failure to provide original images upon request will result in unavoidable delays in publication. Please ensure that you have access to all original microscopy and blot data images before submitting your revision.*** Reviewer #1 (Comments to the Authors (Required)): In this study the authors provide several independent lines of evidence to show that two different immunoglobulin heavy chains are expressed by neurons in the mouse central nervous system. This is clearly a very unexpected finding, as expression of immunoglobulins has been assumed to be restricted to lymphocytes, and I have no doubt that it will be of considerable interest to many neuroscientists. Although the authors are not yet able to explain the functional significance of their findings, they discuss several possible roles for the immunoglobulin heavy chains. These include involvement in oligodendrocyte development, neuronal migration and pathfinding, and the generation and pruning of synapses. The work is of high quality, the findings are convincing and the paper is very well written. P3: the distribution of Ighg3 is interesting, as it is restricted to inhibitory interneurons and shows a very restricted laminar pattern. Can the authors say what proportion of inhibitory neurons in the superficial dorsal horn were Ighg3-positive? Also, can they relate this to any of the neurochemical populations that have been identified in this region? P4: two typos -"lymphocytes" in line 9; "characterised" in the 6th last line.
P5: the last sentence of the 2nd paragraph could be improved. I'm not sure that you can propose an "unknown functional role". P6 3rd last line: "eponyms"? P7: the "Animals" section needs to be tidied up to avoid repetition in the first sentence and clarify the ethical permission.
P8 line 4: "neuropeptide combination" is probably carried over from a previous paper. Fig 5 legend line 9: brown would be better than green to describe the membrane bound form. There is also some red staining in the top two images in part D, which should be removed.

st Authors' Response to Reviewers
August 8, 2021 We would like to thank the reviewer for acknowledging the novelty of our findings and his comments. Please find below our point-by-point reply.
Reviewer #1 (Comments to the Authors (Required)): In this study the authors provide several independent lines of evidence to show that two different immunoglobulin heavy chains are expressed by neurons in the mouse central nervous system. This is clearly a very unexpected finding, as expression of immunoglobulins has been assumed to be restricted to lymphocytes, and I have no doubt that it will be of considerable interest to many neuroscientists. Although the authors are not yet able to explain the functional significance of their findings, they discuss several possible roles for the immunoglobulin heavy chains. These include involvement in oligodendrocyte development, neuronal migration and pathfinding, and the generation and pruning of synapses. The work is of high quality, the findings are convincing and the paper is very well written.
I have only a few minor suggestions for improvement.
P2: it would help to say something about the possible significance of this new finding at the end of the Introduction.
We have added a sentence at the end of the introduction.
P3: the distribution of Ighg3 is interesting, as it is restricted to inhibitory interneurons and shows a very restricted laminar pattern. Can the authors say what proportion of inhibitory neurons in the superficial dorsal horn were Ighg3-positive? Also, can they relate this to any of the neurochemical populations that have been identified in this region?
We agree with the reviewer that the expression pattern of Ighg3 is interesting. We have not yet performed in depth co-expression analysis to determine which of the 15 different types of inhibitory spinal interneurons are co-expressing Ighg3. However, we are planning to follow up on the function of Ighg3 and Ighm including additional in-depth co-expression analysis in future studies.
Has been corrected.
P5: the last sentence of the 2nd paragraph could be improved. I'm not sure that you can propose an "unknown functional role".
We wanted to highlight that, while many different members of the Ig-superfamily are expressed in the nervous system, there is no reference yet of an expression of the name giving members (immunoglobulins) of the Ig-superfamily in neurons. While none of the authors is a native speaker, we thought that the word "eponym" would characterize something or someone, in this case immunoglobulins, as the first of which others are named after. If the Editors or the reviewer feel that this is an incorrect use of the word, we can change it. P7: the "Animals" section needs to be tidied up to avoid repetition in the first sentence and clarify the ethical permission.
We have tidied up the animal section.
P8 line 4: "neuropeptide combination" is probably carried over from a previous paper.
Has been deleted .   Fig 1 legend: "two types of inhibitory . . . spinal neurons". This is not quite correct, as there will be extensive overlap between cells defined by expression of VGAT and GAD67 We agree with the reviewer that this quote is not entirely correct and have modified it accordingly. There is also some red staining in the top two images in part D, which should be removed.
The red staining has been removed and the we changed the description of the membrane bound form to brown. Thank you for submitting your revised manuscript entitled "Expression of Immunoglobulin constant domain genes in neurons of the mouse central nervous system". We would be happy to publish your paper in Life Science Alliance pending final revisions necessary to meet our formatting guidelines.
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