Mechanisms Underlying the Initiation and Dynamics of Neuronal Filopodia: From Neurite Formation to Synaptogenesis - International Review of Cell and Molecular Biology - page 128

initial rise in PIP3 levels within microdomains may thus serve to recruit
WAVE proteins to sites of actin patch formation, which in turn drive the
activation of the Arp2/3 complex. Furthermore, myosin X binds PIP3,
promotes formation of filopodia in a PIP3-binding-dependent manner
( Plantard et al., 2010 ), and may serve to bundle actin filaments together
during the initial stages of filopodia formation (Section 4.2 ). Thus, the ini-
tial rise in PIP3 levels in axonal microdomains may serve an organizational
role in the formation of actin patch precursors to formation of filopodia.
In unpublished work, we have observed that axonal filopodia emerge
after the peak of actin filament accumulation has occurred in patches ( Fig.
3.5 ). The localized PIP3 microdomains follow almost identical dynamics as
the actin patches they give rise to ( Ketschek and Gallo, 2010 ). This obser-
vation thus suggests that the assembly of a filopodium from an actin patch
perhaps does not correlate with the localized increase in PIP3 levels, but
rather with the subsequent decline in PIP3 and actin levels. PIP3 is con-
verted into phosphatidylinositol 4,5-bisphosphate (PIP2) by phosphatases,
notably phosphatase and tensin homolog (PTEN; Park et al., 2010 ). Emer-
gence of filopodia from actin patches may thus correlate with localized
increases in PIP2 levels, as PIP3 is converted to PIP2 during the second
half of the microdomain/patch lifespan. Lee et al. (2010) have suggested
a model for the assembly of filopodia based on PIP2. In this model, PIP2
recruits proteins involved in organizing the filopodial actin bundle and
establishing the tip complex that is thought to control the elongation of the
filopodium (Section 4.2 ). Similarly, endogenous synaptotagmin 1, a synap-
tic vesicle-associated protein, promotes formation of axonal filopodia and
branches ( Greif et al., in press ) and has been shown to bind to phospholipids
(e.g. PIP2; Johnsson and Karlsson, 2012 ). Thus, the initial increase of PIP3
in microdomains drives the formation of actin patches, and, albeit specula-
tive, the subsequent decrease in PIP3 levels and relative localized increase
in PIP2 levels may serve to drive the reorganization of the filaments in the
actin patch into a filopodial bundle and mediate aspects of membrane turn-
over during the emergence of the filopodium (Fig. 3 . 5 B).
The formation of filopodia in neurons is under regulation by extracel-
lular signals. Thus, it stands to reason that a signal that induces filopodia will
likely induce filopodia in the vicinity of the receptors to which it binds. In
the case of nerve growth factor-induced axonal filopodia and actin patches,
patches and filopodia form in proximity to, or in direct colocalization with,
clusters of the TrkA receptor on the surface of axons ( Ketschek and Gallo,
2010 ). TrkA receptors associate with lipid rafts ( Limpert et al., 2007 ), lipid