The Signaling of Neuregulin-Epidermal Growth Factor Receptors and Its Impact on the Nervous System
Round 1
Reviewer 1 Report
In the manuscript entitled “The Signaling Of Nrg-Erbbs And Its Impact On The Nervous System” authors reviewed the action of ErbB receptors focusing on the role of ErbB3, but the information is disordered and sometimes incomplete. Authors should thoroughly revise the manuscript and make sure that everything that the reader needs to know is in the review. I recommend introducing the elements that will be used to discuss each section which is vital for understanding. For this, authors should rewrite the manuscript. In addition, other points need to be addressed before publication.
Major points:
-In the family of ErbB receptor section, ErbB, NRG, HER, and Neu should be defined and explained.
-In the first section, receptors and ligands should be better explained. In fact, ligands for each receptor are not described. Section 6 discusses ErbB3 and myelination and NRG1 is mentioned, however, it is not clear all the NRG (that I have assumed to be neuregulins) isoforms and their ligand activities in ErbB receptors. It is critical for the review to be easily readable that the whole system ErbB receptors and ligands is discussed.
-On page 3 line 113 authors stated that embryonic lethality is caused by ErbB3 null mutation. However, on page 5 line 182: “Interestingly, at birth, ErbB3 mutant mice exhibited normal characteristics, including normal brain mass, and were indistinguishable from the control mice.” It would be advisable to explain what type of mutation in ErbB3 gene these mice had.
-It would be desirable to end every section with a summary of the information given, so the readers have a take-home message.
- Section 8 should begin with a short introduction about glioma characteristics for the readers to follow the manuscript.
-There are sentences without a proper reference. An example page 7 line 303: “ErbB3 overexpression is driven by inheritable promoter methylation or post-transcriptional silencing of the oncosuppressor miR-205 and sustains the malignant phenotype.” Reference should be added.
-The review should include a section about what are the roles of the other ErbB receptors in glioma for a full understanding.
-In the discussion section on page 10 line 454 authors stated that: “Several drugs that target ErbB3 are currently in clinical development, including monoclonal antibodies and small molecule inhibitors. These drugs work by blocking the activation of ErbB3 and downstream signaling pathways, thereby inhibiting cancer cell growth and survival.” What type of cancer cells are they talking about? I think that this should be mentioned in detail. Are there clinical trials with ErbB targeting drugs? This should be an interesting point to add to the review.
Minor points:
-Grammar should be checked. Page 5 line 178: “5. Erbb3 and glia cells (it should say glial cells). There are several minor mistakes to be corrected.
-On page 5 line 179: “The ErBB3 receptor plays a critical role in brain development and its expression begins as early as E16 in the brain, reaching a peak around P20.” Is it Erbb3 or ErBB3?
-In the title and the abstract section, authors should define abbreviations.
Abbreviations used should be defined the first time they are introduced. Please include the definition.
-Page 4 line 144, “At comparable concentration to those on the 143 cellular membrane ErbB3 doesn’t form omo-dimers but auto-oligomers.” This sentence needs revision.
-Page 4 line 158 “The catalytic domain of c-ErbB3 shows a homology sequence of about 60-63% 158 than the other ErbB’s family member.” What is c-ErbB3? It is not explained in the text.
-Grammar should be checked. Page 5 line 178: “5. Erbb3 and glia cells (it should say glial cells). There are several minor mistakes to be corrected.
-Page 4 line 144, “At comparable concentration to those on the 143 cellular membrane ErbB3 doesn’t form omo-dimers but auto-oligomers.” This sentence needs revision.
Author Response
In response to the reviewer's feedback, we have made substantial enhancements to the text's structure and addressed the gaps in information. Furthermore, we have conducted a comprehensive revision of the entire manuscript to ensure it now encompasses all essential details for the reader's comprehension. In line with the reviewer's recommendations, we have thoughtfully integrated the pertinent elements into each section to facilitate the discussion.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
All in all I’d like to compliment the authors for this detailed review regarding the role of Erbbs in the CNS and respective pathologies. The review is extensive and well written. However, there are some minor points I’d like to suggest to improve the review:
- In point 2, the focus lies clearly on ErbB2 and 3. What about ErbB4 and 1? Are there less data available or is it just the same as ErbB2 and 3? The addressed structure and variants are very complex. Maybe a well designed graphic would help to understand similarities and differences between types of ERbBs and would help visualize the postion changes with respective changes in function/signaling/….
- In figure 1, ErbB3 expression is visualized in detail. Why was this molecule picked? A graphic with all ErbBs would be interesting, maybe different colour schemes for different ErbBs.
- Regarding point 5: the E16-timeline etc. are from mouse? The species should be mentioned, if there are some differences between different rodents/mammals. Are there also human data available? At least, if there is no data, this should be addressed
- Maybe an additional graphic would be beneficial for point 7 onwards regarding different variants of ErbBs and function/pathways to visualize this. Or maybe a table?
- “some studiessuggest that” (line 274/275) which studies? Just one mentioned…
- Figure 3 is not very informative in my opinion, many interactions/pathways which are mentioned in the text are missing there, maybe it should be expanded. Also with possible inhibitors to visualize where in signaling inhibitors may work
- Line 307 ff. -> is this all 1 source? Should be indicated
- Why is Afatinib 1 time with capital letter, other times small letter?
- Which source is this? Befor line 333?
- For me it is a bit confusing: in point 8 also signaling is mentioned and explained and point 9 is specially signaling in glioblastoma. Here, differences should be made more clear.
- Which source material is 367 ff. from?
- Regarding promising therapies: which study/source is this? Why is it under “glioblastoma” if there are more or less data from other cancers? This should be separated then. Maybe a table with different therapeutic approaches, kind of cancer, study: human, mice,… and result could be created to give an overview
- Why is there so much focus on ErbB3? For ErbB4 there are also studies regarding GBM… for example ErbB4 in the brain: Focus on high grade glioma, Pitcher et al
Author Response
In response to the reviewer's feedback, we have made substantial enhancements to the text's structure and addressed the gaps in information. Furthermore, we have conducted a comprehensive revision of the entire manuscript to ensure it now encompasses all essential details for the reader's comprehension.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Authors should carefully revise the manuscript again so there are no mistakes.
Here are some that I found:
-Line 39 carcer should say cancer?
-Line 68, authors stated “Neuregulin ligand (NRG)”.
Since NRG was already defined in line 48, it is not necessary to defined it again.
-Also in line 69, authors stated “they hetero-dimerization”
This sentence should be revised.
-There is no reference to Figure 4 or Figure 5 in the text. Authors should include it.
-Line 469, authors stated “Glioblastoma (GBM) is e most common malignant brain tumor in adults,”
It should say Glioblastoma (GBM) is the most…
Authors should carefully revise the manuscript again so there are no mistakes.
Here are some that I found:
-Line 39 carcer should say cancer?
-Line 68, authors stated “Neuregulin ligand (NRG)”.
Since NRG was already defined in line 48, it is not necessary to defined it again.
-Also in line 69, authors stated “they hetero-dimerization”
This sentence should be revised.
-There is no reference to Figure 4 or Figure 5 in the text. Authors should include it.
-Line 469, authors stated “Glioblastoma (GBM) is e most common malignant brain tumor in adults,”
It should say Glioblastoma (GBM) is the most…
Author Response
Reply to Reviewer n.1.
- Authors should carefully revise the manuscript again so there are no mistakes.
We appreciated the precision of the reviewer in the reading of the manuscript that we have revised carefully.
Here are some that I found:
-Line 39 carcer should say cancer?
We replaced “carcer” with “cancer”.
-Line 68, authors stated “Neuregulin ligand (NRG)”.
Since NRG was already defined in line 48, it is not necessary to defined it again.
"In accordance with the reviewer's feedback, we have replaced 'Neuregulin ligand (NRG)” with “NRG".
-Also in line 69, authors stated “they hetero-dimerization”.
This sentence should be revised.
We have revised the sentence, and it now reads, 'They undergo heterodimerization.'
-There is no reference to Figure 4 or Figure 5 in the text. Authors should include it.
We concur with the reviewer's feedback and have incorporated the references pertaining to Figures 4 and 5 into the text.
-Line 469, authors stated “Glioblastoma (GBM) is e most common malignant brain tumor in adults,”
It should say Glioblastoma (GBM) is the most…
We substituted “e” with “the”.
Comments on the Quality of English Language
Authors should carefully revise the manuscript again so there are no mistakes.
Here are some that I found:
-Line 39 carcer should say cancer?
We have replaced “carcer” with “cancer”.
-Line 68, authors stated “Neuregulin ligand (NRG)”.
Since NRG was already defined in line 48, it is not necessary to defined it again.
We have removed “Neuregulin ligand (NRG)” and mentioned “NRG”.
-Also in line 69, authors stated “they hetero-dimerization”.
This sentence should be revised.
We have revised the sentence, “They undergo heterodimerization”.
-There is no reference to Figure 4 or Figure 5 in the text. Authors should include it.
We have included the references in the main text.
-Line 469, authors stated “Glioblastoma (GBM) is e most common malignant brain tumor in adults,”
It should say Glioblastoma (GBM) is the most…
In agree with reviewer we have replace “e” with “the”.
Author Response File: Author Response.pdf
