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 signalregulated 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.

Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases

“…Support for such a role has now come with, the result of a mouse knockout for DUSP6/MKP-3 (Li et al, 2007). Surprisingly, given the severity of the defects seen following morpholino-mediated knockdown of DUSP6/MKP-3 in Zebrafish embryos, mouse embryos lacking this phosphatase do not present with any obvious abnormalities.…”

“…Surprisingly, given the severity of the defects seen following morpholino-mediated knockdown of DUSP6/MKP-3 in Zebrafish embryos, mouse embryos lacking this phosphatase do not present with any obvious abnormalities. However, embryos lacking DUSP6/MKP-3 do show evidence of increased levels of phosphorylated ERK2 in the limb buds and present with a variably penetrant postnatal lethality, skeletal dwarfism, premature fusion of the cranial sutures (craniostynostoses) and hearing loss (Li et al, 2007). All of these features are consistent with increased activity of FGF receptor (FGFR)-mediated signalling pathways although they do not precisely mimic the results of any particular FGF receptor gain of function mutant.…”

Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates

“…Digoxigeninlabeled cRNA probes were prepared from cDNA-containing plasmids or following PCR amplification of 39 untranslated regions (UTRs) from mouse genomic DNA. Erm(Etv5), Fgf8, Fgf10, Fgfr1, and Spry1 probes were described previously (Li et al 2007; Urness et al 2010Urness et al , 2011. Pea3(Etv4) came from IMAGE cDNA 5318783.…”

Physiological Signaling Specificity by Protein Tyrosine Phosphatases

“…For example, MKP-3-deficient mice that survive weaning show skeletal dwarfism, cryaniosynostosis, and developmental defects, which is consistent with MKP-3 being a negative regulator of the Erk pathway downstream of FGF receptor signaling (42). However, these differences have not been observed by others (44).…”

“…The first knockout phenotype of an MKP was that of MKP-1, and the initial assessment of this phenotype supported the idea of redundancy (20). Despite the fact that all the MKPs share a common set of MAPK substrates, the complexity of their regulation at the transcriptional and posttranslational level is broad enough that these enzymes show stark differences in their physiological actions (15,17,42,75,84). The emergence of genetic data now argue strongly against the initial perception of redundancy among the MKPs (Table 1), and compelling evidence for physiological signaling REVIEWS FIGURE 4.…”