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  1. Evaluation Summary:

    This work is of interest to the field of reproduction. Prior to fertilization, spermatozoa undergo a series of morphological and biochemical changes to become fertilization competent, driven by a rapid and poorly understood signaling cascade, culminating in the acrosome reaction. This latter reaction releases to the outside components from a vesicle, the acrosome, in the spermatozoan head and transforms the head plasma membrane so that sperm can fuse with the egg. The work shows that a G protein modulator GIV/Girdin, influences sperm motility and the acrosome reaction. In so doing it is important for fertilization and is one more strategy to control untimely acrosome reaction. The proposed mechanism is well supported by a variety of different experimental approaches.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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  2. Reviewer #1 (Public Review):

    Mammalian sperm are required to mature in the female tract in a process named capacitation and to undergo the acrosome reaction, a unique exocytotic process, that allow sperm to fuse and fertilize the egg. Untimely acrosome reaction is detrimental to capacitation and therefore mechanisms that prevent it are important. This work shows that GIV, a guanine nucleotide-exchange modulator (GEM) for trimeric GTPases, is highly expressed in spermatocytes. It is phosphor-regulated during capacitation in serine and tyrosine residues in mouse and human sperm. Phosphorylation of GIV reported to be located in the flagella and the acrosome in the sperm head, activates its ability to stimulate the PI3K→Akt signaling pathway regulating sperm motility and survival, and in the head controlling premature acrosome reaction. Intracellular Ca2+ oscillations had already been shown to modulate premature acrosome reaction. Interestingly, the work also shows that GIV transcripts are downregulated in the testis and semen of infertile men. The authors reach these conclusions combining KO mice and cell-penetrating peptides. Though the findings are interesting and important, several aspects of their quantitation would require significant improvements (for example, it is not indicated how many independent mice or human samples were used and how many cells were examined). The spatiotemporal segregation of signaling programs in the sperm flagella and head relevant for fertilization are indeed notable.

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  3. Reviewer #2 (Public Review):

    In Reynoso et al. the authors describe how the spatiotemporal phosphorylation of GIV/Girdin in mammalian sperm connects several important signaling cascades that mediate both sperm capacitation and ultimately the acrosome reaction to prepare sperm for fertilization. The central integration of GIV/Girdin as part of the sperm signalome is elegantly demonstrated via detailed fluorescence microscopy with phosphospecific antibodies in both human and mouse sperm, with extensive corroborating evidence from experiments using both knockout mice and biochemical perturbations. I was especially impressed by the use of a TAT transduction system to experimentally measure how wild type and mutant domains of GIV can perturb sperm maturation. I think the authors convincingly support their central tenant that GIV serves dual roles in enhancing PI3K/Akt signaling during capacitation and inhibit cAMP to prevent premature acrosome reaction. The potential transcriptional correlation with human fertility was also interesting, and will likely motivate further research into GIV as a target of infertility and contraception. I believe this report highlights GIV as one of the most highly pleiotropic proteins in sperm, and presents a significant step forward in our understanding of the mammalian fertilization cascade.

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