Mechanisms Underlying the Initiation and Dynamics of Neuronal Filopodia: From Neurite Formation to Synaptogenesis - International Review of Cell and Molecular Biology - page 135

and similarly, these two parameters differ between filopodia as they engage
in different behaviors. Inhibition of myosin II results in longer filopodia
( Lin et al., 1996 ; Gehler et al., 2004 ), consistent with a decrease in retrograde
flow allowing filopodial tips to extend further through actin polymeriza-
tion. In contrast, activation of the RhoA/RhoA-kinase/myosin II pathway
suppresses filopodia formation and extension ( Loudon et al., 2006 ; Gallo,
2006 ), presumably in part by increasing retrograde flow. Ultimately, it will
be important to determine how actin polymerization and retrograde flow
are controlled in individual filopodia on a subsecond timescale. Calcium
can drive myosin II activity through the calmodulin-myosin light chain
kinase pathway ( Takashima, 2009 ) and myosin light chain kinase is found in
axons, growth cones and filopodia ( Kollins et al., 2009 ). It will be of inter-
est to determine if filopodial calcium transients (Section 3.5 ) may regulate
the temporal pattern of filopodial retraction through myosin II activation.
However, filopodial calcium transients can stabilize growth cone filopodia
( Gomez et al., 2001 ), suggesting that they may match the rate of retrograde
flow to that of actin polymerization, thus resulting in a stable filopodial
tip. Alternatively, calcium transients may shut down both retrograde flow
and stabilize filopodial actin filaments ( Lankford and Letourneau, 1989 ). In
contrast, experimental uncaging of calcium in individual filopodia of inver-
tebrate growth cones promotes filopodial elongation instead of stabiliza-
tion ( S. Cheng et al., 2002 ), indicating that under some conditions, calcium
transients may also promote actin polymerization and/or inhibit retrograde
flow. Clearly, much remains to be elucidated with regard to the mechanisms
of spatiotemporal control of filopodial extension and dynamics.
While the mechanisms that control the tip of the filopodium have
received much attention, recent studies have begun to indicate that filopo-
dial dynamics are also likely controlled by events along their shaft. ERM
proteins link actin filaments to the membrane and are found in filopo-
dia. Inhibition of ERM-mediated binding of actin filaments to the mem-
brane increases the rate of actin retrograde flow ( Marsick et al., 2012 ). Thus,
ERM protein may act as a “clutch” linking actin filaments to the mem-
brane and decreasing their retrograde flow ( Giannone et al., 2009 ). Actin
depolymerizing factor/cofilin sever actin filaments and promote pointed
end depolymerization ( Bernstein and Bamburg, 2010 ), and may contrib-
ute to the remodeling of filopodial actin bundles. Drebrin is a protein that
binds actin filaments, and in filopodia is often found in the proximal part
of the filopodium ( Dun and Chilton, 2010 ). Drebrin controls the bind-
ing of a set of other proteins to actin filaments ( Poukkula et al., 2011 ),