{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T15:48:32Z","timestamp":1773416912803,"version":"3.50.1"},"reference-count":68,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004189","name":"Max-Planck-Gesellschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004189","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Mammalian spermatozoa employ calcium (Ca<jats:sup>2+<\/jats:sup>) and cyclic adenosine monophosphate (cAMP) signaling in generating flagellar beat. However, how sperm direct their movement towards the egg cells has remained elusive. Here we show that the Rho small G protein RAC1 plays an important role in controlling progressive motility, in particular average path velocity and linearity. Upon RAC1 inhibition of wild type sperm with the drug NSC23766, progressive movement is impaired. Moreover, sperm from mice homozygous for the genetically variant<jats:italic>t<\/jats:italic>-haplotype region (<jats:italic>t<\/jats:italic><jats:sup><jats:italic>w5<\/jats:italic><\/jats:sup><jats:italic>\/t<\/jats:italic><jats:sup><jats:italic>w32<\/jats:italic><\/jats:sup>), which are sterile, show strongly enhanced RAC1 activity in comparison to wild type (+\/+) controls, and quickly become immotile<jats:italic>in vitro<\/jats:italic>. Sperm from heterozygous (<jats:italic>t\/+<\/jats:italic>) males, on the other hand, display intermediate RAC1 activity, impaired progressive motility and transmission ratio distortion (TRD) in favor of<jats:italic>t<\/jats:italic>-sperm. We show that<jats:italic>t<\/jats:italic>\/+-derived sperm consist of two subpopulations, highly progressive and less progressive. The majority of highly progressive sperm carry the<jats:italic>t<\/jats:italic>-haplotype, while most less progressive sperm contain the wild type (+) chromosome. Dosage-controlled RAC1 inhibition in<jats:italic>t<\/jats:italic>\/+ sperm by NSC23766 rescues progressive movement of (+)-sperm<jats:italic>in vitro<\/jats:italic>, directly demonstrating that impairment of progressive motility in the latter is caused by enhanced RAC1 activity. The combined data show that RAC1 plays a pivotal role in controlling progressive motility in sperm, and that inappropriate, enhanced or reduced RAC1 activity interferes with sperm progressive movement. Differential RAC1 activity within a sperm population impairs the competitiveness of sperm cells expressing suboptimal RAC1 activity and thus their fertilization success, as demonstrated by<jats:italic>t<\/jats:italic>\/+-derived sperm. In conjunction with<jats:italic>t<\/jats:italic>-haplotype triggered TRD, we propose that Rho GTPase signaling is essential for directing sperm towards the egg cells.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009308","type":"journal-article","created":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T18:40:59Z","timestamp":1612464059000},"page":"e1009308","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["RAC1 controls progressive movement and competitiveness of mammalian spermatozoa"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2354-8258","authenticated-orcid":true,"given":"Alexandra","family":"Amaral","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2192-8188","authenticated-orcid":true,"given":"Bernhard G.","family":"Herrmann","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2021,2,4]]},"reference":[{"issue":"6","key":"pgen.1009308.ref001","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1002\/j.1939-4640.2003.tb03123.x","article-title":"Tales from the tail: what do we really know about sperm motility?","volume":"24","author":"RM Turner","year":"2003","journal-title":"J Androl"},{"issue":"1\u20132","key":"pgen.1009308.ref002","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1071\/RD05120","article-title":"Moving to the beat: a review of mammalian sperm motility regulation","volume":"18","author":"RM Turner","year":"2006","journal-title":"Reprod Fertil Dev"},{"issue":"2","key":"pgen.1009308.ref003","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.tcb.2016.10.002","article-title":"Signaling in Sperm: More Different than Similar","volume":"27","author":"UB Kaupp","year":"2017","journal-title":"Trends Cell Biol"},{"issue":"1","key":"pgen.1009308.ref004","doi-asserted-by":"crossref","first-page":"5","DOI":"10.4103\/1008-682X.167716","article-title":"Major regulatory mechanisms involved in sperm motility","volume":"19","author":"R Pereira","year":"2017","journal-title":"Asian J Androl"},{"issue":"Pt 4","key":"pgen.1009308.ref005","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1242\/jcs.051326","article-title":"Flagellar and ciliary beating: the proven and the possible","volume":"123","author":"CB Lindemann","year":"2010","journal-title":"J Cell Sci"},{"issue":"8","key":"pgen.1009308.ref006","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1093\/molehr\/gar034","article-title":"Sperm flagella: comparative and phylogenetic perspectives of protein components","volume":"17","author":"K. 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