Open AccessThe Dual-Specificity Protein Phosphatase DUSP9/MKP-4 Is Essential for Placental Function but Is Not Required for Normal Embryonic Development
Author(s) -
Graham Christie,
David J. Williams,
Fiona MacIsaac,
Robin J. Dickinson,
Ian Rosewell,
Stephen M. Keyse
Publication year - 2005
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.25.18.8323-8333.2005
Subject(s) - biology , dual specificity phosphatase , placenta , embryo , phosphatase , trophoblast , embryonic stem cell , embryogenesis , microbiology and biotechnology , genetics , null allele , allele , kinase , gene , mapk/erk pathway , fetus , pregnancy , phosphorylation
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.