Mechanisms Underlying the Initiation and Dynamics of Neuronal Filopodia: From Neurite Formation to Synaptogenesis - International Review of Cell and Molecular Biology - page 115

The proximal 1/3-1/2 of the filopodial shaft of some neuronal filopodia
appears to be a preferential targeting site for some actin-binding proteins.
Drebrin is an actin-filament-binding molecule that in turn regulates the
ability of other proteins to bind filaments ( Dun and Chilton, 2010 ). In
growth cone and axonal sensory neuron filopodia, the localization of dre-
brin is usually restricted at the proximal filopodial shaft (Fig. 3 .3B). How-
ever, in the growth cones of cultured hippocampal neurons, drebrin does
not appear to localize to filopodia, and in these growth cones, it accumulates
at the interface between the peripheral and central domains ( Mizui et al.,
2009 ). These contrasting observations are from in vitro experiments, and it
is not clear if they reflect a difference between neuron types, or regulation
of drebrin localization by the substratum or growth factors. Septin 7 targets
to the proximal shaft close to but not overlapping with the base of the filo-
podium ( Hu et al., 2012 ; also see Fig. 3.7 ). A similar distribution of septin
7 has been reported for dendritic spines and filopodia ( Tada et al., 2007 ).
Interestingly, both drebrin and septin 7 have been shown to bind microtu-
bules or microtubule-associated proteins (e.g. drebrin binds EB3; Geraldo
et al., 2008; Bazellières et al., 2012 ; Hu et al., 2012 ), and may serve as a
mechanism that promotes the entry of microtubules into filopodia. Their
localization in the proximal filopodium is consistent with this notion as this
is the site where microtubule-actin filament interactions would be initiated.
Indeed, septin 7 promotes the targeting of microtubules into axonal filopo-
dia during the branching of sensory axons ( Hu et al., 2012 ). Tropomodulin
1, an actin-filament-binding protein, also localizes to the proximal segment
of filopodial actin filament bundles ( Fath et al., 2011 ). Tropomodulins cap
the pointed ends of actin filaments and inhibit their depolymerization. The
localization of tropomodulins in the proximal filopodium is thus consistent
with the polarity of filaments in filopodia, and may serve to stabilize the
cytoplasmic ends of filopodial actin filaments.
The filopodial shaft, including the proximal segment, contains a vari-
ety of molecules with relatively homogeneous or heterogeneous distribu-
tions. A major role of filopodia is to act as a sensory structure to detect
extracellular signals. Expectedly, receptors for a variety of cell adhesion,
extracellular molecules and growth factors target to filopodia. As an
example, immunolocalization of the p75 neurotrophin receptor reveals
that it is rather evenly distributed throughout filopodia, while the TrkA
neurotrophin receptor exhibits a more punctate distribution ( Gallo et al.,
1997 ). However, in the case of membrane surface proteins that undergo
extensive membrane traffic, little is known about the relative distributions