Mechanisms Underlying the Initiation and Dynamics of Neuronal Filopodia: From Neurite Formation to Synaptogenesis - International Review of Cell and Molecular Biology - page 132

and greatly impairs formation of filopodia in vivo ( Dwivedy et al., 2007 ).
Ena/VASP proteins cluster the barbed ends of filaments, and can protect the
barbed ends from capping protein thereby allowing their polymerization
( Drees and Gertler, 2008 ). Furthermore, Ena/VASP are found at filopodial
tips throughout the elongation of the filopodium and localized underneath
the membrane at the tip of the filopodium ( Applewhite et al., 2007 ). Simi-
larly, myosin X is involved in the formation of filopodia and targets to sites
of filopodial formation ( Sousa et al., 2006 ; Watanabe et al., 2010 ). One of
the mechanisms through which myosin X promotes formation of filopodia
is to bring actin filaments together into a bundle during the early stages of
filopodial emergence ( Tokuo et al., 2007 ). Fascin binds and bundles parallel
actin filaments and it is required for formation of filopodia ( Svitkina et al.,
2003 ; Jansen et al., 2011 ). Fascin accumulates in emergent filopodia and may
associate with the tip complex ( Vignjevic et al., 2006 ), and cultured neurons
from Drosophila fascin mutants exhibit greatly decreased numbers of axonal
filopodia/branches ( Kraft et al., 2006 ). Thus, any or all of these molecules
may contribute to the reorganization of actin filaments during the formation
of neuronal filopodia. However, it is worth considering that their functions
may be redundant and perhaps engaged in a context-dependent manner
(i.e. myosin X may be required for bundling of filaments during early stages
of the induction of filopodia by signal X but notY, in which case fascin may
be required). Alternatively, the role and requirement of these molecules may
be sequential (i.e. myosin X initiates filament bundling and fascin maintains
it). Finally, CRP1 is an additional actin-bundling protein that also targets to
filopodia and positively contributes to the regulation of neuronal filopodia
in an actin-binding-dependent manner ( Ma et al., 2011 ). Collectively, these
studies indicate that there is likely redundancy in the molecular mechanisms
that can bundle filaments during filopodia formation. It will be of interest
to determine if these different bundling proteins are required at different
stages of filopodial development, and further detailed additional functions
of the proteins that may contribute to the formation of filopodia.
Ultimately, the complement of molecular mechanisms that control reor-
ganization of actin filaments during the emergence of filopodia need to be
understood in the context of the actual underlying ultrastructural changes.
A careful electron microscopic analysis of actin filament organization in
growth cone filopodia revealed that, when detectable, at the base of the
filopodium, one filament has its barbed end oriented toward the base of the
filopodium ( Lewis and Bridgman, 1992 ). The presence of one or more anti-
parallel actin filaments in the filopodial bundles has implications for myosin