Mechanisms Underlying the Initiation and Dynamics of Neuronal Filopodia: From Neurite Formation to Synaptogenesis - International Review of Cell and Molecular Biology - page 110

One model of filopodial formation proposes that actin filaments in pre-
exisiting branched arrays generated by the Arp2/3 actin nucleating complex
are recruited into filopodial bundles ( Svitkina et al., 2003 ). However, exam-
ples of Arp2/3-independent formation of filopodia have been reported
( Faix et al., 2009 ). Furthermore, the Arp2/3-based model was derived from
studies of filopodia that emerge from lamellipodia, and prominent filopodia
emerge from neuronal growth cones even when they are devoid of detect-
able lamellipodial protrusions (e.g. Fig. 3.2 A,C,D). However, it cannot be
ruled out that small nonprotrusive lamellipodial-like structures, similar
to the axonal patches of actin filaments that give rise to axonal filopodia
( Ketschek and Gallo, 2010 ; Spillane et al., 2011 ), may mediate formation of
filopodia in the absence of large lamellipodia (see Goldberg et al., 2000 and
Section 4.1 ). Similarly, consistent with the notion that filopodia arise from
precursors structures, Steketee et al. (2001) provided evidence that both
neuronal and nonneuronal filopodia emerge from cytological structures,
which they termed focal rings . In contrast, another model for the formation
of filopodia posits that the filaments used to generate the filopodium arise
de novo through the action of other actin nucleating systems (e.g. formins)
( Faix et al., 2009 ).
The GTPase Cdc42 is a major regulator of cellular physiology and was
originally shown to drive increases in the number of filopodia in nonneu-
ronal cells ( Nobes and Hall, 1995 ). However, cases of Cdc42-independent
formation of filopodia have been documented ( Faix et al., 2009 ). For exam-
ple, expression of dominant negative Cdc42 does not alter the number of
spinal neuron growth cone filopodia on a polylysine substratum, but blocks
the increase induced by addition of laminin ( Brown et al., 2000 ), suggesting
an extracellular context dependence of the requirement of Cdc42 in filo-
podia. Drebrin is an actin-filament-binding protein, mostly but not solely
expressed in neurons, that can regulate the ability of other actin-binding
proteins to associate with filaments (e.g. cofilin, myosin II; Dun and Chilton,
2010 ). Experimental expression of drebrin in cell lines that do not express
drebrin increases the number of filopodia ( Shirao et al., 1992 ), suggesting
drebrin taps into an existing mechanism. In contrast, depletion of drebrin
in neurons greatly blocks the formation of filopodia ( Dun et al., 2012 ),
indicating it is required for formation of filopodia in neurons but not in
cells that do not normally express it. Similarly, expression of the neuron-
specific proteins GAP-43 or synaptotagmin I leads to filopodia formation
in nonneuronal cells ( Zuber et al., 1989 ; Feany and Buckley, 1993 ). Thus,
different cell types may utilize different sets of “molecular tools” to generate