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: 6.27). 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.

Download full-text

Full-text

Available from: Suzanne L Mansour, Jan 07, 2014
0 Followers
 · 
117 Views
  • Source
    • "The top results for genes enriched following FGF treatment are sets associated with modulation of signaling, such as protein kinases and GTPase regulators, which may function as activators of Ras to promote MEK/ERK signaling. Transcriptional feedback regulation of RTK signaling is well established, particularly the role of DUSPs providing negative feedback for MAPK signaling (Amit et al., 2007; Li et al., 2007; Owens and Keyse, 2007). Indeed, many DUSPs (MAPK phosphatases) are induced in response to both PDGF and FGF treatment at 1 hr (Figure 1—figure supplement 1D), but FGF alone induces the expression of kinases and GTPase regulators at 4 hr, suggesting a distinct role for the FGF response in regulating MEK/ERK activity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Receptor tyrosine kinases (RTKs) signal through shared intracellular pathways yet mediate distinct outcomes across many cell types. To investigate the mechanisms underlying RTK specificity in craniofacial development, we performed RNA-seq to delineate the transcriptional response to platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling in mouse embryonic palatal mesenchyme cells. While the early gene expression profile induced by both growth factors is qualitatively similar, the late response is divergent. Comparing the effect of MEK (Mitogen/Extracellular signal-regulated kinase) and PI3K (phosphoinositide-3-kinase) inhibition, we find the FGF response is MEK-dependent while the PDGF response is PI3K-dependent. Further, FGF promotes proliferation but PDGF favors differentiation. Finally, we demonstrate overlapping domains of PDGF-PI3K signaling and osteoblast differentiation in the palate and increased osteogenesis in FGF mutants, indicating this differentiation circuit is conserved in vivo. Our results identify distinct responses to PDGF and FGF and provide insight into the mechanisms encoding RTK specificity.
    eLife Sciences 05/2015; 4. DOI:10.7554/eLife.07186 · 8.52 Impact Factor
  • Source
    • "miRNA326 0.0002 1.58 times Maintenance and survival of striatal precursor pool TGM7 [16] [17] miRNA181c 0.0029 1.50 times Switch for lineage-to-self-renewal and telomerase expression PTPN11, PTPN22, DUSP6, PBX3, IRF8, and ZEB2 [18] [19] [20] [21] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Dopamine (DA) is one of the key neurotransmitters in the striatum, which is functionally important for a variety of cognitive and motor behaviours. It is known that the striatum is vulnerable to damage from traumatic brain injury (TBI). However, a therapeutic approach has not yet been established to treat TBI. Hence, the present work aimed to evaluate the ability of Normobaric hyperoxia treatment (NBOT) to recover dopaminergic neurons following a fluid percussion injury (FPI) as a TBI experimental animal model. To examine this, mice were divided into four groups: (i) Control, (ii) Sham, (iii) FPI and (iv) FPI+NBOT. Mice were anesthetized and surgically prepared for FPI in the striatum and immediate exposure to NBOT at various time points (3, 6, 12 and 24 hr). Dopamine levels were then estimated post injury by utilizing a commercially available ELISA method specific to DA. We found that DA levels were significantly reduced at 3 hr, but there was no reduction at 6, 12 and 24 hr in FPI groups when compared to the control and sham groups. Subjects receiving NBOT showed consistent increased DA levels at each time point when compared with Sham and FPI groups. These results suggest that FPI may alter DA levels at the early post-TBI stages but not in later stages. While DA levels increased in 6, 12 and 24hr in the FPI groups, NBOT could be used to accelerate the prevention of early dopaminergic neuronal damage following FPI injury and improve DA levels consistently.
    International Journal of Neuroscience 09/2014; DOI:10.3109/00207454.2014.961065 · 1.53 Impact Factor
  • Source
    • "miRNA326 0.0002 1.58 times Maintenance and survival of striatal precursor pool TGM7 [16] [17] miRNA181c 0.0029 1.50 times Switch for lineage-to-self-renewal and telomerase expression PTPN11, PTPN22, DUSP6, PBX3, IRF8, and ZEB2 [18] [19] [20] [21] "
    [Show abstract] [Hide abstract]
    ABSTRACT: The striatum is considered to be the central processing unit of the basal ganglia in locomotor activity and cognitive function of the brain. IGF-1 could act as a control switch for the long-term proliferation and survival of EGF + bFGF-responsive cultured embryonic striatal stem cell (ESSC), while LIF imposes a negative impact on cell proliferation. The IGF-1-treated ESSCs also showed elevated hTERT expression with demonstration of self-renewal and trilineage commitment (astrocytes, oligodendrocytes, and neurons). In order to decipher the underlying regulatory microRNA (miRNA)s in IGF-1/LIF-treated ESSC-derived neurogenesis, we performed in-depth miRNA profiling at 12 days in vitro and analyzed the candidates using the Partek Genome Suite software. The annotated miRNA fingerprints delineated the differential expressions of miR-143, miR-433, and miR-503 specific to IGF-1 treatment. Similarly, the LIF-treated ESSCs demonstrated specific expression of miR-326, miR-181, and miR-22, as they were nonsignificant in IGF-treated ESSCs. To elucidate the possible downstream pathways, we performed in silico mapping of the said miRNAs into ingenuity pathway analysis. Our findings revealed the important mRNA targets of the miRNAs and suggested specific interactomes. The above studies introduced a new genre of miRNAs for ESSC-based neuroregenerative therapeutic applications.
    BioMed Research International 09/2014; 2014:503162. DOI:10.1155/2014/503162 · 2.71 Impact Factor
Show more