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Article
Peer-Review Record

Ptip and the Trr-COMPASS-like Complex Regulate Cardiac Progenitor Cell Division in the Drosophila Embryonic Heart Tube

Int. J. Mol. Sci. 2025, 26(16), 7954; https://doi.org/10.3390/ijms26167954
by Adam J. Farmer 1,2,3, Mark H. Inlow 3,4, Shaad M. Ahmad 1,2,3 and Kristopher R. Schwab 1,2,3,*
Reviewer 1: Anonymous
Reviewer 2: Anonymous
Int. J. Mol. Sci. 2025, 26(16), 7954; https://doi.org/10.3390/ijms26167954
Submission received: 30 June 2025 / Revised: 7 August 2025 / Accepted: 12 August 2025 / Published: 18 August 2025
(This article belongs to the Special Issue Drosophila: A Versatile Model in Biology and Medicine—2nd Edition)

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In the manuscript of "Ptip and the trr-COMPASS-like complex regulate cardiac progenitor cell division in the Drosophila embryonic heart tube", the authors investigated the functions of Trithorax-related (trr) and PAX transcription activation domain interacting protein (Ptip) in the Drosophila embryonic dorsal vessel (heart tube) development. The results reveal potential mechanisms regulating the development of cardiac progenitor cells in fruit flies. I have the following concerns:

Major points:

  1. It is shown in Figures 2 and 3 that the loss of function of Ptip and trr leads to defects in cardiac progenitor cell division. A rescue experiment would be expected.
  2. The genetic interaction between Ptip and Trr in the regulation of cardiac cell division is not really clear. On the other hand, is there any interaction between the two proteins?
  3. The authors should explain more about the seemingly inconsistency that mutations in Drosophila trr lead to defects in cardiac progenitor cell division, but do not affect the level of H3K4 methylation as the mammalian counterpart does.
  4. ChIP-qPCR may help to find out whether Ptip and Trr affect epigenetic modifications on specific genomic regions like Tin or Svp regulatory elements?

Minor points:

  1. The key affected functional domains of Ptip[MI03338], Ptip[C450] (Lines 127, 135) and trr[C2375X], trr[B] (Lines 271-272) need to be shown in the Figures.

      2. Line 11, … evolutionarily conserved … 

Author Response

Reviewer #1

 

In the manuscript of "Ptip and the trr-COMPASS-like complex regulate cardiac progenitor cell division in the Drosophila embryonic heart tube", the authors investigated the functions of Trithorax-related (trr) and PAX transcription activation domain interacting protein (Ptip) in the Drosophila embryonic dorsal vessel (heart tube) development. The results reveal potential mechanisms regulating the development of cardiac progenitor cells in fruit flies. I have the following concerns:

Major points:

  1. It is shown in Figures 2 and 3 that the loss of function of Ptip and trr leads to defects in cardiac progenitor cell division. A rescue experiment would be expected.
  2. The genetic interaction between Ptip and Trr in the regulation of cardiac cell division is not really clear. On the other hand, is there any interaction between the two proteins?
  3. The authors should explain more about the seemingly inconsistency that mutations in Drosophila trr lead to defects in cardiac progenitor cell division, but do not affect the level of H3K4 methylation as the mammalian counterpart does.
  4. ChIP-qPCR may help to find out whether Ptip and Trr affect epigenetic modifications on specific genomic regions like Tin or Svp regulatory elements?

Minor points:

  1. The key affected functional domains of Ptip[MI03338], Ptip[C450] (Lines 127, 135) and trr[C2375X], trr[B] (Lines 271-272) need to be shown in the Figures.
  1. Line 11, … evolutionarily conserved … 

 

Responses

 

We would like to thank the reviewer for their careful reading of our manuscript and appreciate the thoughtful input that they have provided to us. Below we have addressed the concerns and comments from the reviewer item by item.

 

In the manuscript of "Ptip and the trr-COMPASS-like complex regulate cardiac progenitor cell division in the Drosophila embryonic heart tube", the authors investigated the functions of Trithorax-related (trr) and PAX transcription activation domain interacting protein (Ptip) in the Drosophila embryonic dorsal vessel (heart tube) development. The results reveal potential mechanisms regulating the development of cardiac progenitor cells in fruit flies. I have the following concerns:

Major points:

  1. It is shown in Figures 2 and 3 that the loss of function of Ptip and trr leads to defects in cardiac progenitor cell division. A rescue experiment would be expected.

 

Response: We agree with the reviewer that genetic rescue experiments provide additional evidence of observed phenotypes in hypomorphic and amorphic strains while controlling for second site mutations and genetic modifier effects associated with the background of each allele investigated. However, several constraints precluded us from attempting rescue experiments. These included (1) wanting to complete all relevant experiments in order to meet the deadline for this IJMS special issue, (2) the lack of any existing UAS-Ptip transgenes or integrated genomic fragments containing both Ptip and its regulatory elements at other loci that could be readily used, and (3) the time required to construct and examine embryos that were homozygous for the trr mutant allele, while also containing one copy of the svp-lacZ enhancer trap, a mesodermal or cardiac mesoderm-specific GAL4 driver transgene such as twist-GAL4 or tinD-GAL4, and a UAS-trr transgene.

 

Instead, we took a different approach that we believe achieved the same results. In order to ensure that that cardiac progenitor cell division defect phenotypes we observed were solely a consequence of the actual mutations in Ptip and trr genes themselves, and not due to either second site mutations or genetic modifier effects based on the background of the mutant strains, we utilized two different mutant alleles, derived independently on different genetic backgrounds, for each gene. Since both mutant alleles for each gene provided similar and significant frequencies of cell division defects compared to their relevant controls despite having different genetic backgrounds and origins, we believe that this cell division defect phenotype is indeed due to the disruption of function of the gene itself and not second site mutations or modifier effects. Furthermore, insofar as possible, for each mutant allele that we examined, we used the same genetic background strain for the “wildtype” control (e.g. w1118 or svp-lacZ/+ in an attempt to minimize genetic background-based modifier effects).

 

 

  1. The genetic interaction between Ptip and Trr in the regulation of cardiac cell division is not really clear. On the other hand, is there any interaction between the two proteins?

 

Response: We have revised the text in both the manuscript and in the legend for Figure 4J to provide a more clear explanation of this genetic interaction. In addition, for each of the double heterozygote bars in the histogram in Figure 4J, we have shown with dashed red lines what the expected percentage of that category of cell division defects would be if it were just the additive sum of the percentage of errors in both the single heterozygotes. Genetic interactions between two genes for a particular category of cell division were considered synergistic only if the percentage of the observed cell division defects in that category for the double heterozygote for mutant alleles of both genes was significantly greater than the additive effect (the red dashed line) of the percentages for that defect in both of the single heterozygotes.

 

Previous molecular, genetic, and protein-interaction studies have identified both genetic and physical interaction between Ptip and Trr proteins via a COMPASS-like complex in gene regulation within different biological processes and organisms. Additionally, several Drosophila studies have demonstrated that the importance of these complex members in larval and adult heart development and function via cardiac-specific RNAi knockdown (Huang et al, 2022, Zhu et al., 2023, Zhu et al. 2024). Interestingly, Trr-COMPASS-like activity is necessary to maintain H3K4me1 and H3K4me2 at these stages. Considering the evidence that Ptip and Trr interact via a COMPASS-like complex, we hypothesized that this complex may also mediate specific categories of cardiac cell division, which would be reflected in genetic interactions between the genes encoding these proteins. A genetic interaction between both Ptip and Trr at the embryonic stage of heart development is indeed supported by the data in this manuscript and extends the previous findings evaluating the function of these genes within the larval and adult stages.

 

Huang W, Zhu JY, Fu Y, van de Leemput J, Han Z. Lpt, trr, and Hcf regulate histone mono- and dimethylation that are essential for Drosophila heart development. Dev Biol. 2022 Oct;490:53-65. doi: 10.1016/j.ydbio.2022.07.003. Epub 2022 Jul 16. PMID: 35853502; PMCID: PMC10728806.

 

Zhu JY, Lee H, Huang X, van de Leemput J, Han Z. Distinct Roles for COMPASS Core Subunits Set1, Trx, and Trr in the Epigenetic Regulation of Drosophila Heart Development. Int J Mol Sci. 2023 Dec 9;24(24):17314. doi: 10.3390/ijms242417314. PMID: 38139143; PMCID: PMC10744143.

 

Zhu JY, van de Leemput J, Han Z. Distinct roles of COMPASS subunits to Drosophila heart development. Biol Open. 2024 Jul 15;13(10):bio061736. doi: 10.1242/bio.061736. Epub 2024 Oct 17. PMID: 39417277; PMCID: PMC11554255.

 

  1. The authors should explain more about the seemingly inconsistency that mutations in Drosophila trr lead to defects in cardiac progenitor cell division, but do not affect the level of H3K4 methylation as the mammalian counterpart does.

 

Response: We apologize for the confusion that may have arisen in the text and have sought to clarify this confusion by modifying the text where appropriate (please refer to the track changes). It is not surprising that confusion about the chromatin and transcriptional regulatory activities of Drosophila Trr and the mammalian orthologs, KMT2C and KMT2D exist due to multiple in vitro biochemical and in vivo experimental investigations in differing cells and tissues. In our manuscript, we use the term “global” to describe the extent of H3K4 methylation within the nucleus rather than the localization of this mark to specific gene loci. In the literature, several reports do identify a role for Trr and the KMT2C/D orthologs in maintaining global H3K4 methylation in different cells and tissues (Herz et al., 2012) and more specifically within the larva and adult heart (Huang et al, 2022, Zhu et al., 2023, Zhu et al. 2024). In addition, the activity of these genes is necessary to maintain H3K4 methylation at enhancer regions critical for proper gene regulation within Drosophila and mammalian models (Herz et al. 2012, Hu et al., 2013, Lee et al., 2013). Since global H3K4me1 and H3K4me2 levels are not affected in our studies, we surmise that it is the local H3K4 methylation state at cardiac gene-specific loci that is likely affected by the loss of function of these genes, and which in turn dysregulate gene expression. However, further investigation will be necessary to evaluate this hypothesis. 

 

Herz, H.M.; Mohan, M.; Garruss, A.S.; Liang, K.; Takahashi, Y.H.; Mickey, K.; Voets, O.; Verrijzer, C.P.; Shilatifard, A. Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes Dev 2012, 26, 2604-2620, doi:10.1101/gad.201327.112.

 

Hu, D.; Gao, X.; Morgan, M.A.; Herz, H.M.; Smith, E.R.; Shilatifard, A. The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers. Mol Cell Biol 2013, 33, 4745-4754, doi:10.1128/MCB.01181-13.

 

Lee, J.E.; Wang, C.; Xu, S.; Cho, Y.W.; Wang, L.; Feng, X.; Baldridge, A.; Sartorelli, V.; Zhuang, L.; Peng, W.; et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. Elife 2013, 2, e01503, doi:10.7554/eLife.01503.

 

  1. ChIP-qPCR may help to find out whether Ptip and Trr affect epigenetic modifications on specific genomic regions like Tin or Svp regulatory elements?

 

Response: We agree with the reviewer that ChIP-qPCR would be ideal to investigate the effects these genes have on chromatin modifications and subsequent gene expression of key target targets and thank the reviewer for this recommendation. In particular, this would allow us to progress beyond the “globally” unchanged methylation states that we detected in the Ptip and trr mutations and begin investigating the effects of these genes at cardiac gene-specific loci. However, we believe that such an investigation lay beyond the scope of this manuscript which primarily describes the cardiac defects and genetic interactions within the Drosophila embryonic heart tube. Furthermore, these experiments are technically challenging since they would require significant amounts of chromatin from purified embryonic cardiac cells in addition to antibodies against Drosophila Trr and Ptip antibodies which are presently not commercially available. Thus the experimental methodology would require the development and validation of new reagents and procedures for such an approach.

 

Minor points:

  1. The key affected functional domains of Ptip[MI03338], Ptip[C450] (Lines 127, 135) and trr[C2375X], trr[B] (Lines 271-272) need to be shown in the Figures.

 

Response: We have illustrated the effects of the predicted protein structure for each allele in Supplementary Figure S1 to help readers understand the nature of the mutations/lesions. The major domains identified by SUPERFAMILY have been labelled for each protein and the specific lesion has been identified.

 

 

  1. Line 11, … evolutionarily conserved … 

 

Response: This line has been corrected.

 

Reviewer 2 Report

Comments and Suggestions for Authors

Farmer et al.  Ptip and trr

 

The conserved trithorax-related COMPASS-like complex has previously been shown to be involved in heart development and function. COMPASS complexes contain histone methylation activity for H3K4 and in this way control the epigenetic status of cells. As these are ubiquitous activities, it is a general problem to identify functions with specific readouts/phenotypes suitable for investigation. Here the authors focus on the complex member Ptip, which has not been analyzed for embryonic heart development, so far. The specific readout in the study are cells of two lineages, four cells in a row marked by tinman and two x two cells marked by seven-up in every hemisegment. The authors score the number and misarrangement of these cells. In embryos homozygous for Ptip, the authors observe defects in up to about 20% of the hemisegments depending on the specific situation, while wild type embryos exhibit defects in the low percentace range, demonstrating that Ptip is involved in the development of both embryonic lineages similar to trr. In the second experiment the authors describe a dominant genetic interaction as 10–15% of defective hemisegments are scored in embryos double heterozygous for ptip and trr consistent with both proteins acting in a complex.

 

The study provides novel evidence for a function of Ptip in embryonic heart development even that the novelty and progress in understanding of the function of COMPASS remains limited. Given the straight-forward and clear assay and genetics I would recommend to publish the study following a clarification of the following issues.

 

  1. The genetics is not properly described. The authors describe their Ptip mutants as null mutants. This is certainly not the case as a large part of the gene is still present and most likely transcribed even if nonsense mediated decay is taken into account. The authors should also consider a potential maternal contribution. Thus the phenotype described most likely represents a weak / hypomorphic phenotype. I would expect a real null mutant (maternal and zygotic) to show a much stronger phenotype.

I do neither request to generate amorphic (deletion) alleles nor a demonstration of loss of mRNA or protein, because this would be beyond the scope of this focused study. However, the authors should carefully revise their wording and at some point mention the issue of full and partial loss-of-function and a potential maternal contribution.

  1. Scoring and description of the phenotype. The authors should clarify their scoring. The current score “exhibiting defects” include diverse defects such as cell number, cell arrangement and cell positioning. They should distincguish the defects to cell number and other defects at least.
  2. The authors interpret the variation in cell numbers and arrangement as a prove for a defect in cell division without providing direct evidence. For the conclusion as stated in the title. For example, the authors would need to provide evidence by an assay for cell division such as live imaging with a FUCCI reporter or other cell cycle markers. In principle it is conceivable that cells from other lineages are recruited, for example. I do not understand, why the authors use the term “cell division” and not “cell cycle” or “cell proliferation”. In my understanding of the term, “cell division” refers to the last step in mitosis, namely cytokinesis. A defect in cell division would be indicated by aneuploid cells or bi nuclear cells, for example. Their argument for symmetric versus asymmetric cell division is not really clear to me. I do not see how the positioning of cells would allow to differentiate between these two options. I do not request additional assays for cell cycle states, although this would be interesting. As before the authors need to carefully revise their wording and stick to their assays. For example, a possible title would be ….regulate cardiac progenitor cell number in the …..

 

Minor suggestion:

Given the current issues about funding of community services such as FLYBASE, it is mandatory to fully cite these services with a literature citation, at least, to document their importance.   

Author Response

Reviewer #2

 

The conserved trithorax-related COMPASS-like complex has previously been shown to be involved in heart development and function. COMPASS complexes contain histone methylation activity for H3K4 and in this way control the epigenetic status of cells. As these are ubiquitous activities, it is a general problem to identify functions with specific readouts/phenotypes suitable for investigation. Here the authors focus on the complex member Ptip, which has not been analyzed for embryonic heart development, so far. The specific readout in the study are cells of two lineages, four cells in a row marked by tinman and two x two cells marked by seven-up in every hemisegment. The authors score the number and misarrangement of these cells. In embryos homozygous for Ptip, the authors observe defects in up to about 20% of the hemisegments depending on the specific situation, while wild type embryos exhibit defects in the low percentace range, demonstrating that Ptip is involved in the development of both embryonic lineages similar to trr. In the second experiment the authors describe a dominant genetic interaction as 10–15% of defective hemisegments are scored in embryos double heterozygous for ptip and trr consistent with both proteins acting in a complex.

 

The study provides novel evidence for a function of Ptip in embryonic heart development even that the novelty and progress in understanding of the function of COMPASS remains limited. Given the straight-forward and clear assay and genetics I would recommend to publish the study following a clarification of the following issues.

 

  1. The genetics is not properly described. The authors describe their Ptip mutants as null mutants. This is certainly not the case as a large part of the gene is still present and most likely transcribed even if nonsense mediated decay is taken into account.

 

Response: We agree with the reviewer that the effect of the Ptip mutant alleles upon transcript and protein production is unknown and have removed the instances of “null” from the text to prevent confusion by the reader. 

 

 

  1. The authors should also consider a potential maternal contribution. Thus the phenotype described most likely represents a weak / hypomorphic phenotype. I would expect a real null mutant (maternal and zygotic) to show a much stronger phenotype. I do neither request to generate amorphic (deletion) alleles nor a demonstration of loss of mRNA or protein, because this would be beyond the scope of this focused study. However, the authors should carefully revise their wording and at some point mention the issue of full and partial loss-of-function and a potential maternal contribution.

 

Response: We thank the reviewer for this important suggestion and have included relevant material in the discussion section.

 

  1. Scoring and description of the phenotype. The authors should clarify their scoring. The current score “exhibiting defects” include diverse defects such as cell number, cell arrangement and cell positioning. They should distincguish the defects to cell number and other defects at least.

 

 

Response: We thank the reviewer for this constructive suggestion and have revised our manuscript to provide more detail and clarity regarding our criteria for scoring individual hemisegments (see lines 180-201 in page 4). We note that individual hemisegments are scored as being either wildtype or exhibiting any one of three categories of cell division defects—Tin lineage symmetric cell division defects, defects in the earlier symmetric cell division of Svp superprogenitors, and defects in the subsequent asymmetric cell division of Svp progenitor cells—based only on the number of Tin CCs, Svp CCs, and Svp PCs in each of those specific hemisegments. Cell arrangement and cell positioning were not taken into consideration for scoring. To further emphasize that only cell division defects based on cell numbers were being considered, we have changed the relevant description of the axes in Figures 2E,2F, 3F, and 4J from “Percentage of hemisegments exhibiting defects” to “Percentage of hemisegments exhibiting specific cardiac progenitor cell division defects.”  The scoring of each individual hemisegment for every embryo is further tabulated in the Supplementary files Tables S1, S2, and S3, such that other investigators are able to evaluate the data for their own assessment purposes.

 

  1. The authors interpret the variation in cell numbers and arrangement as a prove for a defect in cell division without providing direct evidence. For the conclusion as stated in the title. For example, the authors would need to provide evidence by an assay for cell division such as live imaging with a FUCCI reporter or other cell cycle markers. In principle it is conceivable that cells from other lineages are recruited, for example. I do not understand, why the authors use the term “cell division” and not “cell cycle” or “cell proliferation”. In my understanding of the term, “cell division” refers to the last step in mitosis, namely cytokinesis. A defect in cell division would be indicated by aneuploid cells or bi nuclear cells, for example. Their argument for symmetric versus asymmetric cell division is not really clear to me. I do not see how the positioning of cells would allow to differentiate between these two options. I do not request additional assays for cell cycle states, although this would be interesting. As before the authors need to carefully revise their wording and stick to their assays. For example, a possible title would be ….regulate cardiac progenitor cell number in the …..

 

We appreciate the reviewer raising this question. We opted to use the term “cell division” instead of cell cycle or cell proliferation for the following reasons:

 

  • We quantitated and compared the number of defects in three distinct categories of cell division—symmetric cell division in the Tin lineage, earlier symmetric superprogenitor cell division in the Svp lineage, and later asymmetric cardiac progenitor cell division in the Svp lineage—both for assessing the phenotypic effects of distinct mutant alleles and in genetic interaction assays. We believe that these three distinct types of cell division are indeed best described using the term “cell division”; using terms such as “asymmetric cell lineage” or “symmetric cell proliferation” would sound rather awkward. Note also that our results demonstrate that both Ptip and trr mediate only two of these three categories of cell division.
  • We examined the cells at stage 16, well after all stages of normal cardiac progenitor/superprogenitor cell cycle or cell division would have been complete. Our readout, using nuclei labelled with appropriate antibodies does not lend itself to clearly determining whether the defect occurred at some point during the cell cycle or cytokinesis, Thus we are more comfortable using the catch-all term “cell division defect” instead,
  • If the defect occurs during asymmetric cell division of the Svp progenitor cell, then the result is often an error in cell fate differentiation, a cell becoming a Svp CC instead of the expected Svp PC, or vice versa, without the total number of relevant heart cells being affected. Such a phenotype again, is better described as a “cell division defect” than a “cell proliferation defect.”
  • Finally, our use of the term “cell division” in the context of these defects is consistent with its use by both other investigators and ourselves in previous publications (Park et al., 1998; Han and Bodmer, 2003; Ward and Skeath, 2000; Ahmad et al., 2012; Ahmad et al., 2014; Kump et al., 2021; Hasan et al., 2024; Farmer et al., 2025).

 

We have also tried to provide a more detailed and clear explanation of the symmetric and asymmetric cell division occurring in the developing heart and how to distinguish errors in each of them in lines 159-201(page 4).

 

Park M, Yaich LE, Bodmer R. Mesodermal cell fate decisions in Drosophila are under the control of the lineage genes numb, Notch, and sanpodo. Mech Dev. 1998 Jul;75(1-2):117-26. doi: 10.1016/s0925-4773(98)00098-7. PMID: 9739121.

 

Ward EJ, Skeath JB. Characterization of a novel subset of cardiac cells and their progenitors in the Drosophila embryo. Development. 2000 Nov;127(22):4959-69. doi: 10.1242/dev.127.22.4959. PMID: 11044409.

 

Han Z, Bodmer R. Myogenic cells fates are antagonized by Notch only in asymmetric lineages of the Drosophila heart, with or without cell division. Development. 2003 Jul;130(13):3039-51. doi: 10.1242/dev.00484. PMID: 12756185.

 

Ahmad SM, Tansey TR, Busser BW, Nolte MT, Jeffries N, Gisselbrecht SS, Rusan NM, Michelson AM. Two forkhead transcription factors regulate the division of cardiac progenitor cells by a Polo-dependent pathway. Dev Cell. 2012 Jul 17;23(1):97-111. doi: 10.1016/j.devcel.2012.05.011. PMID: 22814603; PMCID: PMC3401414.

 

Ahmad SM, Busser BW, Huang D, Cozart EJ, Michaud S, Zhu X, Jeffries N, Aboukhalil A, Bulyk ML, Ovcharenko I, Michelson AM. Machine learning classification of cell-specific cardiac enhancers uncovers developmental subnetworks regulating progenitor cell division and cell fate specification. Development. 2014 Feb;141(4):878-88. doi: 10.1242/dev.101709. PMID: 24496624; PMCID: PMC3912831.

 

Kump AJ, Panta M, Schwab KR, Inlow MH, Ahmad SM. The Drosophila Forkhead/Fox transcription factor Jumeau mediates specific cardiac progenitor cell divisions by regulating expression of the kinesin Nebbish. Sci Rep. 2021 Feb 5;11(1):3221. doi: 10.1038/s41598-021-81894-1. PMID: 33547352; PMCID: PMC7864957.

 

Hasan MR, Kump AJ, Stepaniak EC, Panta M, Shashidhar K, Katariya R, Sabbir MK, Schwab KR, Inlow MH, Chen Y, Ahmad SM. Genome-Wide Expression Profiling and Phenotypic Analysis of Downstream Targets Identify the Fox Transcription Factor Jumeau as a Master Regulator of Cardiac Progenitor Cell Division. Int J Mol Sci. 2024 Dec 1;25(23):12933. doi: 10.3390/ijms252312933. PMID: 39684645; PMCID: PMC11641245.

 

Farmer AJ, Katariya R, Islam S, Rayhan MSA, Inlow MH, Ahmad SM, Schwab KR. trithorax is an essential regulator of cardiac Hox gene expression and anterior-posterior patterning of the Drosophila embryonic heart tube. Biol Open. 2025 Apr 15;14(4):bio061919. doi: 10.1242/bio.061919. Epub 2025 Apr 2. PMID: 40172069; PMCID: PMC11993250.

 

Minor suggestion:

Given the current issues about funding of community services such as FLYBASE, it is mandatory to fully cite these services with a literature citation, at least, to document their importance.   

 

Response: We thank the reviewer for this important recommendation. We have included both literature citations and the recommended citations for Flybase, DSHB, and the BDSC. 

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

the paper now is acceptable for its publication.

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