RT Journal Article
SR Electronic
T1 BDNF-Mediated Cerebellar Granule Cell Development Is Impaired in Mice Null for CaMKK2 or CaMKIV
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 8901
OP 8913
DO 10.1523/JNEUROSCI.0040-09.2009
VO 29
IS 28
A1 Manabu Kokubo
A1 Masahiro Nishio
A1 Thomas J. Ribar
A1 Kristin A. Anderson
A1 Anne E. West
A1 Anthony R. Means
YR 2009
UL http://www.jneurosci.org/content/29/28/8901.abstract
AB The Ca2+/calmodulin-activated kinases CaMKK2 and CaMKIV are highly expressed in the brain where they play important roles in activating intracellular responses to elevated Ca2+. To address the biological functions of Ca2+ signaling via these kinases during brain development, we have examined cerebellar development in mice null for CaMKK2 or CaMKIV. Here, we demonstrate that CaMKK2/CaMKIV-dependent phosphorylation of cAMP response element-binding protein (CREB) correlates with Bdnf transcription, which is required for normal development of cerebellar granule cell neurons. We show in vivo and in vitro that the absence of either CaMKK2 or CaMKIV disrupts the ability of developing cerebellar granule cells in the external granule cell layer to cease proliferation and begin migration to the internal granule cell layer. Furthermore, loss of CaMKK2 or CaMKIV results in decreased CREB phosphorylation (pCREB), Bdnf exon I and IV-containing mRNAs, and brain-derived neurotrophic factor (BDNF) protein in cerebellar granule cell neurons. Reexpression of CaMKK2 or CaMKIV in granule cells that lack CaMKK2 or CaMKIV, respectively, restores pCREB and BDNF to wild-type levels and addition of BDNF rescues granule cell migration in vitro. These results reveal a previously undefined role for a CaMKK2/CaMKIV cascade involved in cerebellar granule cell development and show specifically that Ca2+-dependent regulation of BDNF through CaMKK2/CaMKIV is required for this process.