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Vol. 20, Issue 24, 5051-5063, December 15, 2009

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Bone Morphogenetic Protein-6 Promotes Cerebellar Granule Neurons Survival by Activation of the MEK/ERK/CREB Pathway

Bruna Barneda-Zahonero^*,, Alfredo Miñano-Molina^*,, Nahuai Badiola^*,, Rut Fadó^*,, Xavier Xifró^*,, Carlos A. Saura^*,, and José Rodríguez-Alvarez^*,

*Institut de Neurociencies and Departament de Bioquímica i Biología Molecular Universitat Autònoma de Barcelona, 08193 Cerdanyola del Valles, Barcelona, Spain; and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain

Submitted May 26, 2009; Revised October 8, 2009; Accepted October 9, 2009
Monitoring Editor: Marianne Bronner-Fraser

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.

Present address: Departament de Biologia Cellular, Universitat de Barcelona and IDIBAPS, 08036 Barcelona, Spain.

Address correspondence to: Dr. José Rodríguez Alvarez (jose.rodriguez{at}uab.es).

Abbreviations used: CGC, cerebellar granule cell; DIV, days in vitro; K5, 5 mM KCl; K25, 25 mM KCl.