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of membranous and cytoplasmic pools in filopodia. The filopodial shaft
also contains signaling molecules (e.g. focal adhesion kinase (FAK), Rac1/
Cdc42/RhoA;
Renaudin et al., 1999
;
Thies and Davenport, 2003
;
Myers
et al., in press
), most of which are known to regulate the actin cytoskel-
eton and/or substratum attachment. The filopodial shaft exhibits multiple
substratum attachment points (
Steketee and Tosney, 2002
). Interestingly,
inhibition of substratum attachment along filopodia promotes the advance
of adjacent lamellipodia along the shaft of the filopodium (
Steketee and
Tosney, 2002
), indicating that filopodial shaft adhesions negatively regu-
late lamellipodial advance. A major regulator of actin filament turnover,
actin depolymerizing factor/cofilin, also targets to growth cone filopodia
(
Gehler et al., 2004
). Myosin motor proteins are found in filopodia, and
these may contribute to intrafilopodial traffic (myosin I, V, X;
Lewis and
Bridgman, 1996
;
Evans et al., 1997
;
Kerber et al., 2009
) and contractility
(myosin IIA, IIB;
Rochlin et al., 1995
; Fig.
3
.3C). Filopodia have also been
reported to contain MAP1B, a microtubule-associated protein, which,
however, can also bind actin filaments (
Bouquet et al., 2004
). MAP1B in
filopodia may assist in the interactions between actin filaments and micro-
tubules during growth cone guidance and process branching. Filopodia
are sites of active membrane turnover (Section
3.3
), and contain vesicle
and associated proteins with known functions in synaptic vesicle biology
(e.g. synaptotagmin;
Kraszewski et al., 1995
;
Greif et al., in press
) and neu-
rotransmitter recycling systems (e.g. dopamine transporter, vesicular gluta-
mate transporter;
Rao et al., 2012
;
C. Cheng et al., 2002
). Ezrin/Radixin/
Moesin (ERM) proteins also target to filopodia (
Ramesh, 2004
;
Gallo,
2008
;
Antoine-Bertrand et al., 2011
;
Marsick et al., 2012
). ERM proteins
can mediate the attachment of the membrane to actin filaments and are
regulated by phosphorylation, which activates the proteins. Phosphory-
lated forms of ERM proteins preferentially target to filopodial shafts and
positively contribute to the increase in the levels of filopodial β1-integrin
and L1 induced by nerve growth factor in sensory axon growth cones
(Marsick et al., 2012). Conversely, ERM proteins are dephosphorylated in
response to signals that cause growth cone collapse and loss of filopodia
(
Schlatter et al., 2008
;
Gallo, 2008
;
Marsick et al., 2012
). Finally, the shaft
of filopodia can give rise to both lamellipodia and filopodia (Fig.
3
.
1
D and
Fig.
3
.
2
A). The mechanisms regulating the initiation of protrusion along
the filopodial shaft are not well understood. However, activation of phos-
phoinositide 3-kinase promotes the initiation of filopodia both from the
main axon shaft and from the shaft of individual filopodia (
Ketschek and
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