Bone morphogenetic protein-6 promotes cerebellar granule neurons survival by activation of the MEK/ERK/CREB pathway.
Bone morphogenetic proteins (BMPs) have been implicated in the generation and postnatal differentiation of cerebellar granule cells (CGCs). Here, we examined the eventual role of BMPs on the survival of these neurons. Lack of depolarization causes CGC death by apoptosis in vivo, a phenomenon that is mimicked in vitro by deprivation of high potassium in cultured CGCs. We have found that BMP-6, but not BMP-7, is able to block low potassium-mediated apoptosis in CGCs. The neuroprotective effect of BMP-6 is not accompanied by an increase of Smad translocation to the nucleus, suggesting that the canonical pathway is not involved. By contrast, activation of the MEK/ERK/CREB pathway by BMP-6 is necessary for its neuroprotective effect, which involves inhibition of caspase activity and an increase in Bcl-2 protein levels. Other pathways involved in the regulation of CGC survival, such as the c-Jun terminal kinase and the phosphatidylinositol 3-kinase (PI3K)-Akt/PKB, were not affected by BMP-6. Moreover, failure of BMP-7 to activate the MEK/ERK/CREB pathway could explain its inability to protect CGCs from low potassium-mediated apoptosis. Thus, this study demonstrates that BMP-6 acting through the noncanonical MEK/ERK/CREB pathway plays a crucial role on CGC survival.
Institut de Neurociencies and Departament de Bioquímica i Biología Molecular, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Valles, Barcelona, Spain.
Bruna
B
Barneda-Zahonero
Alfredo
A
Miñano-Molina
Nahuai
N
Badiola
Rut
R
Fadó
Xavier
X
Xifró
Carlos A
CA
Saura
José
J
Rodríguez-Alvarez
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D055418:Bone Morphogenetic Protein 6 / Q000494:pharmacology*; D061945:Caspase Inhibitors; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D008954:Models, Biological; D009474:Neurons / Q000166:cytology* / Q000201:enzymology; D011188:Potassium / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051785:Smad Proteins / Q000378:metabolism
D055418:Bone Morphogenetic Protein 6; D061945:Caspase Inhibitors; D017362:Cyclic AMP Response Element-Binding Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051785:Smad Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D011188:Potassium