Roles of Nuclear Orphan Receptors TR2 and TR4 during Hematopoiesis

Round 1

Reviewer 1 Report

This manuscript focuses on testicular nuclear receptors 2 and 4 (TR2, TR4), also known as NR2C1 and NR2C2, belong to the nuclear receptor superfamily.
Although classified as orphan receptors, several natural molecules, their metabolites, and synthetic compounds can activate them, such as PUFAs.
There is not much information in the literature about these receptors. Therefore, this manuscript provides actualized information. More figures and tables may improve summarizing the most relevant finding.


(1) Figure 1 has "?" symbols. I am not sure they belong there.
(2) Line 101. Please correct typo "a1.nd"
(3) It may be useful if a diagram of haematopoiesis is shown.
(4) The relationship with diabetes could be expanded.
(5) Is it possible to expand the information regarding the role of orphan receptors in cancer and their targetting by drugs? For example, in prostate cancer.
(6) Ther frequency of mutation of NR2C1 is low in all types of cancer (based on cBioportal), and just found in 4-5% of cases of uterine carcinosarcoma, sarcoma, and endometrial carcinoma. Regarding NR2C2 is mutated in 4-6% of uterine corpus endometrial carcinosarcoma and bladder urothelial carcinoma. Is it possible to check the clinical relevance of changes of gene expression, methilation, copy-number and LOH, and mutation of these to genes in more detail?
(7) Is it possible to show figures with the function and mechanism of TR2 and TR4?
(8) Is it possible to show the 3D structure of TR2 and TR4, and the possible ligands?
(9) Is it possible to model the drugs that target TR2 and TR4 molecules or their pathways?
(10) Please refer to https://www.proteinatlas.org/ENSG00000120798-NR2C1/pathology
(11) Please refer to https://www.proteinatlas.org/ENSG00000177463-NR2C2/pathology
(12) Please refer to Parris, T.Z. Pan-cancer analyses of human nuclear receptors reveal transcriptome diversity and prognostic value across cancer types. Sci Rep 10, 1873 (2020). https://doi.org/10.1038/s41598-020-58842-6

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

In this review article, the authors reviewed and discussed the roles of nuclear orphan receptors TR2 and TR4 during Hematopoiesis.

Comments:

The reviewer has some concerns as follows:

1.     There are some structural confusions in the writing of this manuscript. There are only two sections in the text of this manuscript: “Introduction” and “Summary”, although there are four subsections (1.1-1.4) for Introduction section. The entire manuscript seems to lack coherence, making it difficult to read and understand.

2.     In line 1, the type of this manuscript is “review”, but not “article”. It should be revised.

3.     In Figures 1 and 2, some detailed information can be indicated in the legends, such as in Fig. 1, brief explains the ε, Gg, Ag, and β types in human and εy, βh1, βmajor, and βminor in mouse; in Fig. 2, brief explains the correlation of PGC1α/β and TR2/TR4.

4.     Importantly, there are too many self-citations in this manuscript, which should be avoided as much as possible. In this manuscript, there are 72 references in which have 13 references referred to authors' earlier publications.

Author Response

Please see the uploaded response attachment.

Thank you!

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

This revised manuscript has a great improvement and can be accepted.