Pruning Dendrites

Science Signaling  02 Aug 2011:
Vol. 4, Issue 184, pp. ec213
DOI: 10.1126/scisignal.4184ec213

The signaling pathways that mediate dendrite outgrowth in neurons have been characterized in greater detail than those that promote dendrite retraction and pruning. Puram et al. uncovered a role for Ca2+/calmodulin-dependent protein kinase IIβ (CaMKIIβ) in dendrite patterning. Rat granule neurons overexpressing a constitutively active mutant of CaMKIIβ developed shorter, less branched dendrites. In contrast, granule, hippocampal, and cerebral cortical neurons developed longer, more branched dendrites when transfected with short hairpin RNAs (shRNAs) directed against CaMKIIβ, effects that were also observed after shRNA-mediated knockdown of CaMKIIβ in the cerebellar cortices of rats and organotypic cerebellar slices. Time-lapse imaging revealed that overexpression of the constitutively active CaMKIIβ mutant increased the number of retraction events, whereas CaMKIIβ knockdown increased the number of extension events. The inhibitory effect of CaMKIIβ on dendrite growth required its catalytic activity and a domain that localized the protein to the centrosome through interaction with PCM1 (pericentriolar material 1). Knockdown of PCM1 in cerebellar cortices of rats phenocopied the effects of knockdown of CaMKIIβ and resulted in longer dendrites in granule neurons. CaMKIIβ phosphorylated Ser51 of Cdc20, a substrate-targeting component of the ubiquitin ligase APC (anaphase-promoting complex), thereby inducing dispersion of Cdc20 from the centrosome and preventing degradation of APC substrates. Neurons with Cdc20 localized at the centrosome had longer dendrites than those in which Cdc20 was not localized at the centrosome. Thus, CaMKIIβ activity at the centrosome alters the access of Cdc20-APC to its substrates, which triggers dendrite retraction and limits dendrite outgrowth.

S. V. Puram, A. H. Kim, Y. Ikeuchi, J. T. Wilson-Grady, A. Merdes, S. P. Gygi, A. Bonni, A CaMKIIβ signaling pathway at the centrosome regulates dendrite patterning in the brain. Nat. Neurosci. 14, 973–983 (2011). [PubMed]