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Molecular and Cellular Biology, September 2005, p. 8323-8333, Vol. 25, No. 18
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.18.8323-8333.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Dual-Specificity Protein Phosphatase DUSP9/MKP-4 Is Essential for Placental Function but Is Not Required for Normal Embryonic Development{dagger}

Graham R. Christie,1,{dagger} David J. Williams,1,{ddagger} Fiona MacIsaac,1 Robin J. Dickinson,1 Ian Rosewell,2 and Stephen M. Keyse1*

Cancer Research UK Molecular Pharmacology Unit, Biomedical Research Centre, Level 5, Ninewells Hospital and Medical School, Dundee DD1 9SY,1 Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, United Kingdom2

Received 16 March 2005/ Returned for modification 26 April 2005/ Accepted 2 July 2005

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.

* Corresponding author. Mailing address: Cancer Research UK Molecular Pharmacology Unit, Biomedical Research Centre, Level 5, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, United Kingdom. Phone: 44 1382 632622. Fax: 44 1382 669993. E-mail: Stephen.Keyse{at}cancer.org.uk.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} G.R.C. and D.J.W. contributed equally to this study.

Molecular and Cellular Biology, September 2005, p. 8323-8333, Vol. 25, No. 18
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.18.8323-8333.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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