title: Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice.
abstract: Successful embryo implantation requires functional luminal epithelia to establish uterine receptivity and blastocyst-uterine adhesion. During the configuration of uterine receptivity from prereceptive phase, the luminal epithelium undergoes dynamic membrane reorganization and depolarization. This timely regulated epithelial membrane maturation and precisely maintained epithelial integrity are critical for embryo implantation in both humans and mice. However, it remained largely unexplored with respect to potential signaling cascades governing this functional epithelial transformation prior to implantation. Using multiple genetic and cellular approaches combined with uterine conditional Rac1 deletion mouse model, we demonstrated herein that Rac1, a small GTPase, is spatiotemporally expressed in the periimplantation uterus, and uterine depletion of Rac1 induces premature decrease of epithelial apical-basal polarity and defective junction remodeling, leading to disrupted uterine receptivity and implantation failure. Further investigations identified Pak1-ERM as a downstream signaling cascade upon Rac1 activation in the luminal epithelium necessary for uterine receptivity. In addition, we also demonstrated that Rac1 via P38 MAPK signaling ensures timely epithelial apoptotic death at postimplantation. Besides uncovering a potentially important molecule machinery governing uterine luminal integrity for embryo implantation, our finding has high clinical relevance, because Rac1 is essential for normal endometrial functions in women.
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.|University of the Chinese Academy of Sciences, Beijing 100039, PR China.
authors.forename: Z
authors.initials: Z
authors.lastname: Tu
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.|University of the Chinese Academy of Sciences, Beijing 100039, PR China.
authors.forename: T
authors.initials: T
authors.lastname: Cui
authors.affiliation: Department of Pharmacology, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.|State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100039, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Ran
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.|State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100039, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Bao
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Lydon
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: F
authors.initials: F
authors.lastname: DeMayo
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.
authors.forename: S
authors.initials: S
authors.lastname: Kong
authors.affiliation: Department of Pharmacology, Zhejiang University, Hangzhou 310058, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D010064:Embryo Implantation / Q000235:genetics* / Q000502:physiology; D004717:Endometrium / Q000254:growth & development / Q000378:metabolism; D004848:Epithelium / Q000254:growth & development / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014599:Uterus / Q000378:metabolism / Q000502:physiology; D054462:p21-Activated Kinases / Q000096:biosynthesis / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C513242:Etv5 protein, mouse; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D014157:Transcription Factors; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein