期刊
DEVELOPMENT
卷 134, 期 1, 页码 167-176出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.02701
关键词
Mkp3; Pyst1; dual specificity phosphatase; craniosynostosis; middle ear; otic capsule; mouse
资金
- NIDCD NIH HHS [R01 DC002043-09, R01 DC004185, R01DC02043, R01 DC002043-12, R01 DC002043-11, R01 DC002043-10A2, R01 DC002043, R01DC04185] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007464, T32 GM007464-30, T32 GM007464-28, T32 GM007464-29] Funding Source: Medline
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007464] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS [R01DC004185, R01DC002043] Funding Source: NIH RePORTER
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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