title: Targeted inactivation of murine Ddx3x: essential roles of Ddx3x in placentation and embryogenesis.
abstract: The X-linked DEAD-box RNA helicase DDX3 (DDX3X) is a multifunctional protein that has been implicated in gene regulation, cell cycle control, apoptosis, and tumorigenesis. However, the precise physiological function of Ddx3x during development remains unknown. Here, we show that loss of Ddx3x results in an early post-implantation lethality in male mice. The size of the epiblast marked by Oct3/4 is dramatically reduced in embryonic day 6.5 (E6.5) Ddx3x-/Y embryos. Preferential paternal X chromosome inactivation (XCI) in extraembryonic tissues of Ddx3x heterozygous (Ddx3x-/+) female mice with a maternally inherited null allele leads to placental abnormalities and embryonic lethality during development. In the embryonic tissues, Ddx3x exhibits developmental- and tissue-specific differences in escape from XCI. Targeted Ddx3x ablation in the epiblast leads to widespread apoptosis and abnormal growth, which causes embryonic lethality in the Sox2-cre/+;Ddx3xflox/Y mutant around E11.5. The observation of significant increases in γH2AX and p-p53Ser15indicates DNA damage, which suggests that loss of Ddx3x leads to higher levels of genome damage. Significant upregulation of p21WAF1/Cip1and p15Ink4bresults in cell cycle arrest and apoptosis in Ddx3x-deficient cells. These results have uncovered that mouse Ddx3x is essential for both embryo and extraembryonic development.
authors.affiliation: Institute of Biochemistry and Molecular Biology.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Institute of Biochemistry and Molecular Biology.
authors.forename: Chieh-Hsiang
authors.initials: CH
authors.lastname: Chan
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences.|VYM Genome Research Center, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Institute of Biochemistry and Molecular Biology.
authors.forename: Yin-Shuan
authors.initials: YS
authors.lastname: Tsai
authors.affiliation: Institute of Biochemistry and Molecular Biology.
authors.forename: Tsung-Yuan
authors.initials: TY
authors.lastname: Tsai
authors.affiliation: Institute of Biochemistry and Molecular Biology lryou@ym.edu.tw yhwulee@nctu.edu.tw.|Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 300, Taiwan.
authors.forename: Yan-Hwa
authors.initials: YH
authors.lastname: Wu Lee
authors.affiliation: Institute of Biochemistry and Molecular Biology lryou@ym.edu.tw yhwulee@nctu.edu.tw.|VYM Genome Research Center, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: You
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D053487:DEAD-box RNA Helicases; D004249:DNA Damage / Q000235:genetics; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D006801:Humans; D051379:Mice; D010929:Placentation / Q000235:genetics*; D011247:Pregnancy; D020365:RNA Helicases / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: C493957:Cdkn1a protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D053487:DEAD-box RNA Helicases; C514697:Ddx3x protein, mouse; D020365:RNA Helicases