The dual-specificity protein phosphatase DUSP9/MKP-4 is essential for placental function but is not required for normal embryonic development.
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.
Christie
Graham R
GR
Cancer Research UK Molecular Pharmacology Unit, Biomedical Research Centre, Level 5, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, United Kingdom.
Williams
David J
DJ
Macisaac
Fiona
F
Dickinson
Robin J
RJ
Rosewell
Ian
I
Keyse
Stephen M
SM
D000483:Alleles; D000818:Animals; D002875:Chromosomes; D054637:Dual-Specificity Phosphatases; D004622:Embryo, Mammalian / Q000166:cytology; D047108:Embryonic Development; D005260:Female; D017353:Gene Deletion; D005804:Genes, Lethal; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D010766:Phosphorylation; D010920:Placenta / Q000196:embryology / Q000201:enzymology*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*
D020929:Mitogen-Activated Protein Kinase Kinases; D054637:Dual-Specificity Phosphatases; C484491:Dusp9 protein, mouse; D017027:Protein Tyrosine Phosphatases