title: Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development.
abstract: Mitogen-activated protein kinase (MAPK) pathways are major mediators of extracellular signals that are transduced to the nucleus. MAPK signaling is attenuated at several levels, and one class of dual-specificity phosphatases, the MAPK phosphatases (MKPs), inhibit MAPK signaling by dephosphorylating activated MAPKs. Several of the MKPs are themselves induced by the signaling pathways they regulate, forming negative feedback loops that attenuate the signals. We show here that in mouse embryos, Fibroblast growth factor receptors (FGFRs) are required for transcription of Dusp6, which encodes MKP3, an extracellular signal-regulated kinase (ERK)-specific MKP. Targeted inactivation of Dusp6 increases levels of phosphorylated ERK, as well as the pERK target, Erm, and transcripts initiated from the Dusp6 promoter itself. Finally, the Dusp6 mutant allele causes variably penetrant, dominant postnatal lethality, skeletal dwarfism, coronal craniosynostosis and hearing loss; phenotypes that are also characteristic of mutations that activate FGFRs inappropriately. Taken together, these results show that DUSP6 serves in vivo as a negative feedback regulator of FGFR signaling and suggest that mutations in DUSP6 or related genes are candidates for causing or modifying unexplained cases of FGFR-like syndromes.
authors.affiliation: Department of Human Genetics, University of Utah, 15 N 2030 E RM 2100, Salt Lake City, UT 84112-5330, USA.
authors.forename: Chaoying
authors.initials: C
authors.lastname: Li
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Scott
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Hatch
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Tian
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Mansour
mesh_terms: D000483:Alleles; D000818:Animals; D002460:Cell Line; D054642:Dual Specificity Phosphatase 6; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000166:cytology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011247:Pregnancy; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse; D017027:Protein Tyrosine Phosphatases