Article

Li C, Scott DA, Hatch E, Tian X, Mansour SL.. Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Development 134: 167-176

Department of Human Genetics, University of Utah, 15 N 2030 E RM 2100, Salt Lake City, UT 84112-5330, USA.
Development (Impact Factor: 6.46). 02/2007; 134(1):167-76. DOI: 10.1242/dev.02701
Source: PubMed

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.

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Available from: Suzanne L Mansour, Jan 07, 2014
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    • "Unlike the neighbouring cortical hem, a secondary organizer of the hippocampal primordium (Mangale et al. 2008), which displays strong expression for both Wnt and Bmp molecules (Grove et al. 1998), the EmT showed strong expression for Wnts but low levels of expression for members of the Bmp family. Fgfs showed restricted expression in the EmT but expression of Mkp3, a downstream negative regulator of Fgf signalling (Li et al. 2007), was more widespread. This compares to the restricted expression of Fgf8 in relation to the widespread expression domain of Mkp3 in the isthmus (Echevarria et al. 2005), a secondary organizer of the midbrain–hindbrain region (Martinez 2001). "
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