BMP Signaling Pathway in Dentin Development and Diseases
Vidya Chandrasekaran
Round 1
Reviewer 1 Report
The paper is a comprehensive review of the role of BMP signaling during development and disease. Overall, the paper is well-written. Here are some edits to make the paper more readable.
1) Introduction : Since the paper in a later section mentions timing of human teeth development, a few sentences comparing mouse and human teeth development/timeline here would be good.
2) Figure 1: arrow/arrowhead showing inter-tubular dentin, dentinal tubule in panel C.
3) Figures with expression data - Since the data are not generated as part of this paper, it would be good to have a reference in the legend to indicate source of the figures.
4) BMP family : Figure 2 shows the ligands, receptors and Smads - but there is no mention of the receptors or Smads in this section. It would be good to have a sentence that talks about the signaling here.
5) BMP ligand expression: For most BMPs (except BMP-6), only transcript data is described. Is there protein expression data available? If so, add them. Are other members of the BMP family not found in teeth? It would good to start this section with a sentence that lists the BMPs present in teeth. Only BMP-7 is noted as present in humans. What about other BMPs?
6) Section 2.3 and figures associated- This section describes details about BMP-9, BMP-10, BMP-14 - their crystal structure. Since these BMPs are not listed as present in teeth, it is not clear why this discussion is included. It would be good to clarify or focus this paragraph only on BMPs present in the teeth. Similarly in BMP signaling section 4, end of pg. 24 (lines 883 onwards) there is detailed discussion of other members. Streamlining the BMP signaling to information relevant to teeth formation would help the reader.
7)Section 3 lists downstream genes but does not include any connection to BMP in this section. That information is included in a section 4.1. Also, till section 4, there is no mention of the BMP signaling pathway - so downstream signaling is unclear. It would be better to reorganize section 3 and section 4 . i)BMP signaling during tooth development - Smad-dependent signaling
ii)Downstream genes - expression and effect in BMP KO
iii) BMPs signaling that is Smad-independent
7) Extra spaces in line 120 and line 415.
8) Line 1211 - "tune" role?
Author Response
Reviewer #1
- Introduction: Since the paper in a later section mentions timing of human teeth development, a few sentences comparing mouse and human teeth development/timeline here would be good.
Answer: We appreciate the reviewer’s comment. In the revised manuscript, we added information of human tooth development.
- Figure 1: arrow/arrowhead showing inter-tubular dentin, dentinal tubule in panel C.
Answer: Arrows showing inter-tubular dentin and dentinal tubule in Figure 1C were added in the revised manuscript.
- Figures with expression data - Since the data are not generated as part of this paper, it would be good to have a reference in the legend to indicate source of the figures.
Answer: Thank you for the reviewer’s suggestion. Each figure legend was added at least one reference except for figure 7. The data from figure 7 has not be published.
- BMP family: Figure 2 shows the ligands, receptors and Smads - but there is no mention of the receptors or Smads in this section. It would be good to have a sentence that talks about the signaling here.
Answer: The new sentence was added in the revised manuscript.
- BMP ligand expression: For most BMPs (except BMP-6), only transcript data is described. Is there protein expression data available? If so, add them. Are other members of the BMP family not found in teeth? It would good to start this section with a sentence that lists the BMPs present in teeth. Only BMP-7 is noted as present in humans. What about other BMPs?
Answer: Thank you for raising the excellent questions. Besides using inti-RNA probes of Bmp2, Bmp-4 and Bmp-7, immunohistochemistry assay was used to detect expression of Bmp-2, Bmp-4 and Bmp-7 proteins during tooth development. The data were added in the revised manuscript.
We have searched for gene expression and biological functions of other BMPs family during tooth development and formation using Pudmed.gov website such as BMP9 + tooth and Bmp10 + tooth. We have found 11 Bmp9 related to tooth, BMP10 + tooth, 0 No results were found; BMP11 + tooth, 1 result was found; BMP12 + tooth, 2 results were found; BMP13 + tooth, no results were found; BMP14 + tooth, no results were found; BMP15 + tooth, no results were found. As BMP-2, BMP-4, BMP-7 have been commonly used to study their roles during tooth development and their signaling pathways, we mainly focused on their roles in tooth development.
BMPs present in teeth are listed in Table 1.
Besides expression of BMP-7 in human teeth, expression of BMP-2, BMP-3 and BMP-4 genes were also investigated in human tooth germs. The data were added to the revised manuscript.
- Section 2.3 and figures associated- This section describes details about BMP-9, BMP-10, BMP-14 - their crystal structure. Since these BMPs are not listed as present in teeth, it is not clear why this discussion is included. It would be good to clarify or focus this paragraph only on BMPs present in the teeth. Similarly in BMP signaling section 4, end of pg. 24 (lines 883 onwards) there is detailed discussion of other members. Streamlining the BMP signaling to information relevant to teeth formation would help the reader.
Answer: Thank you for the reviewer’s comments. Data of the three dimensions of BMP-9, MP-10, BMP-14 proteins were removed from the revised manuscript. Section 4 was rewritten and more focused on tooth information.
- Section 3 lists downstream genes but does not include any connection to BMP in this section. That information is included in a section 4.1. Also, till section 4, there is no mention of the BMP signaling pathway - so downstream signaling is unclear. It would be better to reorganize section 3 and section 4. i)BMP signaling during tooth development - Smad-dependent signaling.
Answer: Thank you for the reviewer’s comments. Sections 2, 3 and 4 were rewritten in the revised manuscript. It includes Smad-dependent and Smad-independent signal pathways in dentin formation.
- ii) Downstream genes - expression and effect in BMP KO.
Answer: The information was added to the revised manuscript.
iii) BMPs signaling that is Smad-independent
Answer: Thank you for correction. The mistake was corrected.
- Extra spaces in line 120 and line 415.
Answer: The mistakes were corrected in the revised manuscript.
- Line 1211 - "tune" role?
Answer: Word “tune” was changed to “accurate”.
Reviewer 2 Report
The manuscript showed the BMP signal pathway in dentin development and diseases. The authors summarized the BMP signaling pathway in odontoblast differentiation and dentin formation, including the expression of the BMP family and the implicated downstream genes. It also described dentin diseases when the BMP family and downstream genes are damaged during dentin development.
It is an excellent review regarding understanding the BMP signaling pathway in odontoblast differentiation and dentin formation during tooth development. However, there are a few suggestions to improve it as follows.;
1. Please increase the figure resolution.
2. Please correct the tissue display line in Figure 1 (ex; enamel lined in dentin)
3. In paragraphs 2.1 and 2.2, Schematic representation is suggested to summarize the BMP family gene expression pattern in dental tissue and cells during tooth development. It is expected to increase understanding of this review. (For example; see figure 6 in reference 28 of this review or figure 1 of DOI:10.1155/2018/7549160)
4. The title of this review is “BMP signal pathway in dentin development and diseases.” The description of the BMP family and downstream gene expression pattern has been well documented, but the definition of diseases is lacking. It is necessary to supplement the explanation of dentin disease caused by a defect in the BMP family gene (BMP2-7 and its receptor). Furthermore, the description of dentin diseases and BMP gene expression during dentin development was separated. Therefore, it is suggested to explain the diseases that occur when each gene has a defect at the end of each gene expression section. It is a way to increase the understanding of the review.
Author Response
The reviewer #2
- Please increase the figure resolution.
Answer: Thank you for the reviewer’s comment. The figure resolution was increased in the revised manuscript.
- Please correct the tissue display line in Figure 1 (ex; enamel lined in dentin)
Answer: The error was corrected.
- In paragraphs 2.1 and 2.2, Schematic representation is suggested to summarize the BMP family gene expression pattern in dental tissue and cells during tooth development. It is expected to increase understanding of this review. (For example; see figure 6 in reference 28 of this review or figure 1 of DOI:10.1155/2018/7549160).
Answer: We appreciate the reviewer’s comments. Gene expression pattern of Bmps was summarized in Table1.
- The title of this review is “BMP signal pathway in dentin development and diseases.” The description of the BMP family and downstream gene expression pattern has been well documented, but the definition of diseases is lacking. It is necessary to supplement the explanation of dentin disease caused by a defect in the BMP family gene (BMP2-7 and its receptor). Furthermore, the description of dentin diseases and BMP gene expression during dentin development was separated. Therefore, it is suggested to explain the diseases that occur when each gene has a defect at the end of each gene expression section. It is a way to increase the understanding of the review.
Answer: Thank the reviewer’s comments. In the revised manuscription, we re-written the original manuscript. After each Bmp and its receptor gene expression, we added gene mutations of Bmps and their receptors are associated with tooth defects in humans and mice.
We greatly appreciate time effort as well as kind help and support! Thank you very much!
