Mechanisms Underlying the Initiation and Dynamics of Neuronal Filopodia: From Neurite Formation to Synaptogenesis - International Review of Cell and Molecular Biology - page 125

formation are not well understood. This section reviews current thinking
of the mechanisms that determine how a micron to submicron domain
of the neuronal plasma membrane becomes the site of the formation of a
filopodium.
The establishment of filopodial asymmetries preceding turning have
been shown in the context of gradients of BDNF and lysophosphatidic
acid (LPA) mediated growth cone attraction and repulsion, respectively
( Yuan et al., 2003 ), and also glutamate chemoattraction ( Zheng et al., 1996 ).
Interestingly, gradient application of these signals induces filopodial asym-
metries without changing the mean number of growth cone filopodia, indi-
cating a redistribution of the sites of filopodial formation at growth cones.
Surprisingly, gradients of 2,3-butanedione monoxime (BDM), considered
to be a nonspecific pharmacological inhibitor of myosins, also induced
asymmetry in growth cone filopodia without affecting the total number of
filopodia. These observations indicate that growth cones have a mechanism
to redistribute the sites of filopodia formation while maintaining baseline
levels of filopodia during gradient-mediated guidance.
Surprisingly, although as noted by the work of Bray and Chapman (1985)
filopodia form heterogeneously along the growth cone perimeter, little is
known about the mechanism that determines the sites of filopodia forma-
tion at growth cones. The focal ring filopodial initiation system described
by Tosney et al. ( Steketee et al., 2001 ) provides insights into subcellular
specializations that underlie the initiation of filopodia at growth cones, but
does unveil the mechanism by which these sites are determined. However,
the focal rings correlate with sites of substratum adhesion ( Steketee et al.,
2001 ). At the growth cone, adhesion sites are dynamic and are referred
to as point contacts ( Renaudin et al., 1999 ). Thus, the mechanisms that
control adhesion sites at growth cones may also regulate the sites of filopo-
dial formation. Indeed, during growth cone guidance, extracellular attrac-
tants and repellents asymmetrically regulate growth cone adhesions sites
( Myers and Gomez, 2011 ) and filopodial distribution (Section 3.3 ). Micro-
tubule dynamics control a variety of aspects of the establishment of cell
polarity and migration, including substratum attachment sites ( Kaverina and
Straube, 2011 ). Similar to the distribution of sites of filopodia formation, in
growth cones, the + tips of microtubules are usually aligned with the main
axis of axon extension. Microtubule dynamics may therefore contribute, at
least in part, to the determination of sites of filopodia formation.
The determination of the site of formation of filopodia along axons and
dendrites is somewhat better understood. While the growth cone exhibits