Molecular Systems Biology Peer Review Process File
An Oct4-Sall4-Nanog network controls developmental progression in the preimplantation mouse embryo Meng How Tan, Kin Fai Au, Denise E Leong, Kira Foygel, Wing H. Wong, Mylene Yao Corresponding author: Wing Hung Wong, Stanford University Review timeline:
Submission date: Editorial Decision:
01 October 2011 04 November 2011
Appeal : Editorial Decision: Revision received: Editorial Decision: Revision received: Editorial Decision: Revision received: Accepted:
06 December 2011 20 December 2011 31 July 2012 18 September 2012 05 November 2012 06 November 2012 13 November 2012 30 November 2012
Transaction Report: (Note: With the exception of the correction of typographical or spelling errors that could be a source of ambiguity, letters and reports are not edited. The original formatting of letters and referee reports may not be reflected in this compilation.)
1st Editorial Decision
04 November 2011
Thank you again for submitting your work to Molecular Systems Biology. We have now heard back from the three referees who agreed to evaluate your manuscript. As you will see from the reports below, the referees raise substantial concerns on your work, which, I am afraid to say, preclude its publication in Molecular Systems Biology. While the reviewers appreciated the topic and goals of this work, they all felt that the main conclusions remained rather weakly supported, and that fundamental technical issues cast significant doubt on the biological relevance of these findings. Most importantly, the reviewers raised concerns about potential non-specific or off-targets effects of morpholino treatments, with the first reviewer noting troubling discrepancies with knockout and knockdown phenotypes previously reported in the literature. Additional issues were raised related to the selection of modeling parameters and your ability to rigorously distinguish measurement/experimental error from biological noise. Given these concerns, and the low level of support from the reviewers, unfortunately, I see no other choice than to return the manuscript with the message that we cannot offer to publish it. In any case, thank you for the opportunity to examine your work. I hope that the points raised in the reports will prove useful to you and that you will not be discouraged from submitting future work to Molecular Systems Biology. Sincerely, Editor - Molecular Systems Biology
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Molecular Systems Biology Peer Review Process File
Reviewer #1 (Remarks to the Author): While the intent of Tan et al in this article, to define the downstream targets of Oct4, Nanog, and Sall4 in mouse pre-implantation development, is certainly an interesting topic worthy of investigation, I am afraid that the quality of the data has something to be desired. The major issue I have is in the effects of the knock downs, I am unconvinced the phenotypes are a true reflection of loss of these factors but instead are indirect consequences of either microinjection or off-target effects or both. The entire manuscript is based on the subsequent analysis of these knockdowns. There are publications on the zygotic knock outs for all three factors though the authors surprisingly do not even reference these earlier, highly relevant works. In all these knock outs, embryos do progress to the blastocyst stage. The potential advantage of a knockdown approach is the removal/inhibition of maternal mRNA that may be present. It is known that there is indeed maternal Oct4 and Sall4 in the mouse oocyte but there is no maternal Nanog mRNA or protein. Thus the knock down of zygotic Nanog should not present a phenotype earlier than that found in the Nanog null embryos. Nanog null embryos survive to at least the blastocyst stage (Mitsui et al (2003) Cell 113:631; Silva et al (2009) Cell 138:722) yet only
