TY - JOUR
T1 - MKP3 mediates the cellular response to FGF8 signalling in the vertebrate limb
AU - Kawakami, Yasuhiko
AU - Rodríguez-León, Joaquín
AU - Koth, Christopher M.
AU - Büscher, Dirk
AU - Itoh, Tohru
AU - Raya, Ángel
AU - Ng, Jennifer K.
AU - Esteban, Concepción Rodríguez
AU - Takahashi, Shigeru
AU - Henrique, Domingos
AU - Schwarz, May Fun
AU - Asahara, Hiroshi
AU - Izpisúa Belmonte, Juan Carlos
N1 - Funding Information:
We thank G. Martin for providing limb-specific Fgf4;Fgf8 double-knockout mouse embryos, C. Nuesslein Volhard for the mutant zebrafish dackel, M. Aoki and P. Vogt for the constitutively active Akt construct, T. Jessell for the chick Pea3 and Er81 clones, E. Nishida for the constitutively active Mek1 clone, I. Dubova for his expertise and help with zebrafish, G. Sternik for his assistance with the microscopic analyses, and M. Tsuda for assistance with experiments. J.R.L. is supported by a fellowship from the Fundação Calouste Gulbenkian. T.I. is supported by a JSPS Postdoctoral Fellowship for Research Abroad, Japan. C.M.K. is partly supported by a postdoctoral fellowship from the Canadian Institutes of Health Research, J.K.N. is supported by an NIH training grant, and A.R. is partly supported by a postdoctoral fellowship from the Ministerio de Educación, Cultura y Deporte, Spain. H.A. is supported by the Arthritis Foundation and the Japan Science and Technology Cooperation. This work was supported by grants from BioCell, Fundacao Calouste Gulbenkian e Fundacao para Ciencia e Technologia, the Arthritis Foundation, the G. Harold and Leila Y. Mathers Charitable Foundation, the National Science Foundation, and the National Institutes of Health.
PY - 2003/6/1
Y1 - 2003/6/1
N2 - The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol-3-OH kinase (PI(3)K)/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 PI(3)K/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.
AB - The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol-3-OH kinase (PI(3)K)/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 PI(3)K/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.
UR - http://www.scopus.com/inward/record.url?scp=0038713378&partnerID=8YFLogxK
U2 - 10.1038/ncb989
DO - 10.1038/ncb989
M3 - Review article
C2 - 12766772
AN - SCOPUS:0038713378
SN - 1465-7392
VL - 5
SP - 513
EP - 519
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 6
ER -