Mechanisms Underlying the Initiation and Dynamics of Neuronal Filopodia: From Neurite Formation to Synaptogenesis - International Review of Cell and Molecular Biology - page 100

diameter. Microtubules serve as the major tracks for the transport of organ-
elles and proteins in developed axons and dendrites, and likely have a similar
role during the initial stages of process formation. Indeed, both the redis-
tribution of stabilized microtubules and the entry of microtubules through
dynamic instability into the protrusions of early stage neurons contribute to
the maturation of these protrusions into processes depending on the neuro-
nal type ( Smith, 1994b ; Dent et al., 2007 ). Interestingly, a similar dependence
on microtubule redistribution or dynamic instability has been reported for
the de novo formation of axon branches from preexisting axons ( Gallo and
Letourneau, 1999 ; Dent and Kalil, 2001 ), which may share similarities with
the initial formation of the axon from the cell body. Regardless of whether
microtubules are targeted to filopodia through redistribution or dynamic
instability, collectively, these studies identify the penetration of filopodia by
microtubules as a fundamental step in the formation of axons and dendrites.
Studies of the molecular mechanism that coordinates the actin fila-
ment and microtubule cytoskeleton during minor process formation have
identified molecules that link the two cytoskeletal systems. MAP2c is a
microtubule associated protein, which, however, can also bind and crosslink
actin filaments into bundles, as characteristically found in filopodia ( Roger
et al., 2004 ). MAP2c targets to nascent neuronal processes and expression
of MAP2c mutants that fail to bind microtubules, or protein kinase A,
impairs process formation in hippocampal neurons ( Dehmelt et al., 2003 ).
Additional studies have shown that the actin filament binding property of
MAP2c is also required for MAP2c to promote process formation ( Roger
et al., 2004 ), indicating that it may act to physically link microtubules and
actin filaments. Drebrin is an actin-filament-binding protein that is highly
expressed in brain tissue ( Dun and Chilton, 2010 ). Drebrin regulates the
actin cytoskeleton by binding to filaments and altering the ability of other
proteins to bind the filaments. However, drebrin also binds EB3 ( Geraldo
et al., 2008 ; Bazellières et al., 2012 ), a protein that specifically binds the +
tips of microtubules when they are polymerizing. The interaction between
EB3 and drebrin may serve to target microtubule tips into filopodia during
early stages of process formation ( Geraldo et al., 2008 ). While much remains
to be learned about how microtubules and actin filaments are coordinated
during early process formation, these studies point to the merging theme
that molecules which bind both cytoskeletal components, directly or indi-
rectly, are a major regulatory point.
Regulation of actin filaments underlies the initial formation of filopodia,
and subsequent minor process extension, from neuronal cell bodies. The