title: Nrk, an X-linked protein kinase in the germinal center kinase family, is required for placental development and fetoplacental induction of labor.
abstract: The complete mechanism of labor induction in eutherian mammals remains unclear. Although important roles for the fetus and placenta in triggering labor have been proposed, no gene has been shown to be required in the fetus/placenta for labor induction. Here we show that Nrk, an X-linked gene encoding a Ser/Thr kinase of the germinal center kinase family, is essential in the fetus/placenta for labor in mice. Nrk was specifically expressed in the spongiotrophoblast layer, a fetus-derived region of the placenta, and Nrk disruption caused dysregulated overgrowth of the layer. Due to preferential inactivation of the paternally derived X chromosome in placenta, Nrk heterozygous mutant placentas exhibited a similar defect to that in Nrk-null tissues when the wild-type allele was paternally derived. However, the phenotype was weaker than in Nrk-null placentas due to leaky Nrk expression from the inactivated X chromosome. Crossing of Nrk-null females to wild-type and Nrk-null males, as well as uterine transfer of Nrk-null fetuses to wild-type females, revealed that pregnant mice exhibit a severe defect in delivery when all fetuses/placentas are Nrk-null. In addition, Nrk was not expressed in female reproductive tissues such as the uterus and ovary, as well as the fetal amnion and yolk sac, in pregnant mice. Progesterone and estrogen levels in the maternal circulation and placenta, which control the timing of labor, were unaffected upon Nrk disruption. We thus provide evidence for a novel labor-inducing fetoplacental signal that depends on the X chromosome and possibly arises from the placenta.
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Denda
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Nakao-Wakabayashi
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Okamoto
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kitamura
authors.affiliation: Biomolecular Engineering, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Je-Young
authors.initials: JY
authors.lastname: Ryu
authors.affiliation: Biomolecular Engineering, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Yoh-Ichi
authors.initials: YI
authors.lastname: Tagawa
authors.affiliation: Department of Reprogramming Science, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ichisaka
authors.affiliation: Department of Reprogramming Science, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama 226-8501, Japan. Electronic address: makomada@bio.titech.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komada
mesh_terms: D000483:Alleles; D000818:Animals; D003433:Crosses, Genetic; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007743:Labor, Obstetric / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010920:Placenta / Q000378:metabolism*; D021041:Placental Circulation / Q000502:physiology; D011247:Pregnancy / Q000235:genetics / Q000378:metabolism*; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D011270:Pregnancy, Animal / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014960:X Chromosome / Q000235:genetics / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011257:Pregnancy Proteins; C411848:Nik related kinase; D017346:Protein Serine-Threonine Kinases