Mechanisms Underlying the Initiation and Dynamics of Neuronal Filopodia: From Neurite Formation to Synaptogenesis - International Review of Cell and Molecular Biology - page 104

microtubules to penetrate into the P-domain thereby promoting engorge-
ment (discussed further in Section 5.2 ). The final phase is termed consoli-
dation and occurs at the growth cone neck (Fig. 3 . 1 A). Consolidation is
characterized by the sharp decline in protrusive activity as the growth cone
transitions into the axon shaft. As noted above, the growth cone is a highly
polarized structure and consolidation is required to keep the growth cone
polarized at the tip of the extending axon. The axon advances through
sequential reiteration of these three phases, while also maintaining a polar-
ized growth cone at its tip. Guidance is thought to occur through the regu-
lation of all three phases of axon extension. Through the spatiotemporal
control of the protrusion, engorgement and consolidation phases, extracel-
lular signals can redirect the extension of the axon.
A role for filopodia in the regulation of the rate of axon extension rate
(i.e. distance/unit time), independent of growth cone guidance, has not been
unequivocally described. Indeed, depending on the substratum neurons are
cultured on ( Abosch and Lagenaur, 1993 ), or the developmental age of the
neurons ( Jones et al., 2006 ), axons can extend at intermediate to normal
rates in the absence of actin filaments all together, sometimes even at faster
rates ( Ruthel and Hollenbeck, 2000 ). However, the extension of the axon is
strictly dependent on the forward advance of microtubules during engorge-
ment, regardless of whether actin filaments are present or not ( Letourneau
et al., 1987 ; Jones et al., 2006 ). In contrast, a requirement for actin filaments
in the guidance of axons is well established. In vitro and in vivo studies
revealed a fundamental role for actin filaments, and presumably filopodia,
in the ability of axons to respond to extracellular cues ( Dent and Gertler,
2003 ). In vitro contact of a single filopodium with a guidance cue is suf-
ficient to reorient the growth cone, and thus change the direction of axon
extension ( Gomez and Letourneau, 1994 ; Gallo et al., 1997 ). Similarly, in
order for an axon to extend over a nonpermissive region of the substratum
in vitro (e.g. a nonpermissive stripe between two permissive regions), the
filopodia of the growth cone must be able to reach across the nonpermis-
sive region to contact a permissive region and extend over the nonpermis-
sive region ( Hammarback and Letourneau, 1986 ). Live imaging studies of
growth cone guidance in response to contact with “guidepost” cells in the
limb buds of grasshopper embryos have revealed that this guidance is medi-
ated by contact of single filopodia with the guide-post cells ( O'Connor and
Bentley, 1993 ; discussed further in Section 5 ). While undergoing guidance
to their targets in vivo, axonal growth cones exhibit a striking variety of
morphologies, depending on context. As a rule-of-thumb, the growth cones