Mechanisms Underlying the Initiation and Dynamics of Neuronal Filopodia: From Neurite Formation to Synaptogenesis - International Review of Cell and Molecular Biology - page 131

the mother filaments. A similar scenario, where two actin nucleators act
cooperatively in forming filopodia, has been reported for the DAAM for-
min and the Arp2/3 complex in Drosophila neurons ( Gonçalves-Pimentel
et al., 2011 ).
The capping of the rapidly polymerizing barbed ends of actin filaments
prevents polymerization. Capping proteins have a role in the formation and
dynamics of filopodia. Eps8 is a barbed end capping protein involved in
the induction of axonal filopodia by BDNF ( Menna et al., 2009 ). BDNF
signaling through the MAPK pathway decreases the capping property of
Eps8 and, in turn, promotes formation of axonal filopodia. Ena/VASP pro-
teins inhibit capping of actin filament barbed ends during the extension
of filopodia in fibroblasts. The EVH2 domain of Ena/VASP contains the
anticapping activity, domains for binding actin and for persistent targeting
to filopodial tips, and is sufficient to induce filopodia in nonneuronal cells,
but not in neurons ( Applewhite et al., 2007 ). However, netrin signaling
through PKA regulates Ena/VASP-dependent formation of filopodia along
axons and growth cones ( Lebrand et al., 2004 ). These considerations suggest
that in neurons, capping is regulated differently than in nonneuronal cells,
and that the Ena/VASP functions mediated by the EVH2 domain may not
be sufficient to elicit the formation of neuronal filopodia. The difference in
these mechanisms between neurons and nonneuronal cells may reflect the
biological requirement of rapid and reversible formation of filopodia by
neurons in response to relevant extracellular signals (e.g. BDNF and netrin).
In contrast to a lamellipodium, or an actin patch, which contain actin
filaments arranged in a range of geometries forming an interconnected
meshwork ( Lewis and Bridgman, 1992 ; Spillane et al., 2011 ), the mature
filopodium is characterized by a parallel array of actin filaments with their
barbed ends pointing toward the tip of the filopodium. How are nucleated
actin filaments reorganized to give this to this architecture? Clearly, one or
more mechanisms exist to bundle the filaments together during the early
stages of formation of the filopodium. Ena/VASP, myosin X and fascin may
all contribute to this process although the roles of myosin X and fascin in
neurons are not well understood compared to Ena/VASP. The tips of actin-
filament-based extension exhibit electron dense accumulations at their tips,
which are generally referred to as tip complexes ( DeRosier and Tilney,
2000 ), and actin filament bundling may occur in this subcompartment. Ena/
VASP and myosin X are likely components of the tip complex. Depletion
of Ena/VASP proteins blocks the formation of axonal and growth cone
filopodia in response to the chemoattractant netrin (Lebrand et al., 2004)