The dual-specificity protein phosphatase DUSP9/MKP-4 is essential for placental function but is not required for normal embryonic development

Graham R. Christie, David J. Williams, Fiona MacIsaac, Robin J. Dickinson, Ian Rosewell, Stephen M. Keyse

    Research output: Contribution to journalArticle

    54 Citations (Scopus)

    Abstract

    To elucidate the physiological role(s) of DUSP9 (dual-specificity phosphatase 9), also known as MKP-4 (mitogen-activated protein kinase [MAPK] phosphatase 4), the gene was deleted in mice. Crossing male chimeras with wild-type females resulted in heterozygous (DUSP9+/–) females. However, when these animals were crossed with wild-type (DUSP9+/y) males none of the progeny carried the targeted DUSP9 allele, indicating that both female heterozygous and male null (DUSP9–/y) animals die in utero. The DUSP9 gene is on the X chromosome, and this pattern of embryonic lethality is consistent with the selective inactivation of the paternal X chromosome in the extraembryonic tissues of the mouse, suggesting that DUSP9/MKP4 performs an essential function during placental development. Examination of embryos between 8 and 10.5 days postcoitum confirmed that lethality was due to a failure of labyrinth development, and this correlates exactly with the normal expression pattern of DUSP9/MKP-4 in the trophoblast giant cells and labyrinth of the placenta. Finally, when the placental defect was rescued, male null (DUSP9–/y) embryos developed to term, appeared normal, and were fertile. Our results indicate that DUSP9/MKP-4 is essential for placental organogenesis but is otherwise dispensable for mammalian embryonic development and highlights the critical role of dual-specificity MAPK phosphatases in the regulation of developmental outcomes in vertebrates.
    Original languageEnglish
    Pages (from-to)8323-8333
    Number of pages11
    JournalMolecular and Cellular Biology
    Volume25
    Issue number18
    DOIs
    Publication statusPublished - Sep 2005

    Keywords

    • Embryonic development
    • Placenta enzymology
    • Protein tyrosine phosphatases physiology
    • DUSP9/MKP-4

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