Mechanisms Underlying the Initiation and Dynamics of Neuronal Filopodia: From Neurite Formation to Synaptogenesis - International Review of Cell and Molecular Biology - page 130

rafts may organize receptor systems in the neuronal membrane and con-
tribute to the determination of the sites of filopodia formation. It is worth
considering, however, that although sites of axonal filopodia formation in
response to nerve growth factor codistribute with TrkA clusters, only a sub-
set of surface membrane TrkA clusters give rise to filopodia at any given
time. An additional level of spatial specificity in this system is likely attrib-
utable to the positioning of axonal mitochondria. Treatment with nerve
growth factor greatly increases the colocalization of sites of actin patch and
filopodia formation with axonal mitochondria, and mitochondrial respira-
tion is required for the effects of nerve growth factor ( Ketschek and Gallo,
2010 ). Collectively, these studies indicate that the determination of the site
of formation of an axonal filopodium is likely due to the spatial conver-
gence of multiple factors (e.g. lipid rafts, microdomains of PIP3 signaling,
axonal mitochondria).
4.2. Actin Nucleation and Reorganization during the
Initiation of Neuronal Filopodia
Actin filaments in neurons are very dynamic and constantly turning over.
The first step in the formation of an actin filament is the nucleation of
the filament from the pool of soluble actin monomers. A role for Arp2/3
in nucleating the actin patch precursors to the formation of axonal and
dendritic filopodia is fairly well established ( Korobova and Svitkina, 2008 ;
Mingorance-Le Meur and O'Connor, 2009 ; Spillane et al., 2011 ). However,
the role of Arp2/3 in regulating growth cone filopodia remains controver-
sial ( Strasser et al., 2004 ; Korobova and Svitkina, 2008 ; Norris et al., 2009 ;
Gonçalves-Pimentel et al., 2011 ). Cordon bleu is an additional actin nucle-
ating system that is highly expressed in the nervous system and has a role
in the regulation of neuronal morphogenesis ( Ahuja et al., 2007 ). Cordon
bleu brings together actin monomers forming a seed for continued fila-
ment polymerization. Cordon bleu and Arp2/3 act independently and their
contribution to actin filament levels is additive in in vitro assays. Analysis of
the in vitro development of axon length and branching using hippocampal
neurons revealed a contributing role for cordon bleu in the formation of
axon branches but not axon length ( Ahuja et al., 2007 ). A specific role of
cordon bleu in the regulation of neuronal filopodia has not been inves-
tigated. However, as initiation of axonal filopodia is the first step in the
formation of axon branches, it seems likely that cordon bleu may regulate
axonal filopodia. Possibly, cordon bleu along with Arp2/3 may nucleate
filaments that contribute to actin patch formation. Arp2/3 forms branched
filaments from preexisting mother filaments, and cordon bleu may provide