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MKP3 mediates the cellular response to FGF8 signalling in the vertebrate limb
Yasuhiko Kawakami1, Joaquín Rodríguez-León, Christopher M Koth
1The Salk Institute for Biological Studies, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037-1099, USA.
Abstract:
The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol-3-OH kinase (PI3K)/Akt pathways are involved in the regulatory mechanisms of several cellular processes including proliferation, differentiation and apoptosis. Here we show that during chick, mouse and zebrafish limb/fin development, a known MAPK/ERK regulator, Mkp3, is induced in the mesenchyme by fibroblast growth factor 8 (FGF8) signalling, through the PI3K/Akt pathway. This correlates with a high level of phosphorylated ERK in the apical ectodermal ridge (AER), where Mkp3 expression is excluded. Conversely, phosphorylated Akt is detected only in the mesenchyme. Constitutively active Mek1, as well as the downregulation of Mkp3 by small interfering RNA (siRNA), induced apoptosis in the mesenchyme. This suggests that MKP3 has a key role in mediating the proliferative, anti-apoptotic signalling of AER-derived FGF8.
Insights
Fibroblast growth factor 8 (FGF8) signaling induces Mkp3 in limb development mesenchyme via the PI3K/Akt pathway. Mkp3 mediates FGF8
Area of Science:
- Developmental Biology
- Molecular Biology
- Cell Signaling
Background:
- Mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol-3-OH kinase (PI3K)/Akt pathways regulate cellular processes.
- These pathways are crucial for cell proliferation, differentiation, and apoptosis.
- Fibroblast growth factor 8 (FGF8) signaling plays a role in limb development.
Purpose of the Study:
- To investigate the role of Mkp3, a MAPK/ERK regulator, in chick, mouse, and zebrafish limb/fin development.
- To elucidate the signaling pathway through which FGF8 induces Mkp3.
- To understand Mkp3's function in mediating FGF8's proliferative and anti-apoptotic effects.
Main Methods:
- Analysis of Mkp3 induction during limb/fin development in chick, mouse, and zebrafish embryos.
- Investigation of FGF8 signaling and its downstream effects on PI3K/Akt and MAPK/ERK pathways.
- Use of constitutively active Mek1 and small interfering RNA (siRNA) to downregulate Mkp3.
- Assessment of apoptosis in the mesenchyme following manipulation of Mkp3 levels.
Main Results:
- Mkp3 is induced in the mesenchyme by FGF8 signaling, mediated by the PI3K/Akt pathway.
- Phosphorylated ERK is high in the apical ectodermal ridge (AER) where Mkp3 is excluded.
- Phosphorylated Akt is detected specifically in the mesenchyme.
- Mkp3 downregulation or constitutive Mek1 activation leads to mesenchyme apoptosis.
Conclusions:
- Mkp3 acts as a key mediator of FGF8 signaling in limb/fin development.
- Mkp3 plays a critical role in promoting cell proliferation and preventing apoptosis in the mesenchyme.
- The interplay between FGF8, PI3K/Akt, and Mkp3 is essential for regulating limb development.