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segment of filopodia; septin 7 and drebrin. Drebrin binds to EB3 ( Geraldo
et al., 2008 ; Bazellières et al., 2012 ), a protein that specifically associates
with the actively polymerizing tips of microtubules ( Galjart, 2010 ). Over-
expression and depletion of drebrin increase and decrease, respectively, the
number of axonal filopodia and branches in vitro and in vivo ( Dun et al.,
2012 ; A. Ketschek and G. Gallo, data not shown). While it is not yet clear
whether the association of drebrin with EB3 may have a functional role
in targeting microtubules into axonal filopodia, this mechanism is worth
considering in future studies aimed at detailing the mechanistic aspects of
drebrin function in axons. Septin 7 is required for axon collateral branch
formation ( Hu et al., 2012 ). Furthermore, septin 7 was found to bind
both purified actin filaments and microtubules. Neither overexpression
nor depletion of septin 7 affected the formation of axonal filopodia, sug-
gesting that its actin filament binding does not functionally regulate actin
dynamics during the formation of filopodia, but may serve to target it to
filopodia. In contrast, septin 7 overexpression and depletion increased and
decreased the percentage of axonal filopodia that contained microtubules,
respectively, indicating that septin 7 is involved in either the targeting or
the retention of microtubules in filopodia during the early stages of branch
formation. Since both drebrin and septin 7 localize to the proximal por-
tions of filopodia, they may have complementary or individual roles in
the regulation of microtubules in filopodia. Septin 7 is found at the base
of filopodia while drebrin extends further into the proximal filopodial
shaft. Thus, septin 7 may act to promote microtubule entry into filopodia,
while drebrin may promote their retention in filopodia, or assist in guiding
the polymerizing EB3-decorated microtubule tip further into the filopo-
dium. Interestingly, septin 7 is retained at the base of established branches
( Fig. 3.7 ), suggesting it may have a continued role in targeting or mainte-
nance of microtubules in branches.
Similar to the regulation of microtubule targeting into growth cone
filopodia, kinesins and microtubule-associated proteins have also been
involved in the formation and elongation of axon branches. Depletion of
kinesin-12 decreases the number of axonal filopodia and collateral branches
( Liu et al., 2010 ), through unknown mechanisms. However, kinesin-12 was
found to associate with actin, suggesting it may link microtubules to actin
or perhaps regulate actin dynamics in an unexpected manner. In con-
trast, knockout of the kinesin KIF2A does not alter the number of axon
collateral branches but results in longer branches ( Homma et al., 2003 ).
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