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during neuronal competition for survival (
Deppmann et al., 2008
). These
results suggest that feedback loops mediated by local exocytosis of Trk re-
ceptors and local endocytosis of neurotrophin signaling endosomes poten-
tiate local neurotrophin signaling (e.g.,
Fig. 2.2
) and may be necessary to
amplify such signals
in vivo
to direct the direction of growth.
One of the fundamental questions underlying growth cone guidance is
how do growth cones integrate many signals together? Numerous signaling
molecules and receptors have been identified in neurons whose activity and
localization are regulated by selective exo- and endocytosis (
Bartoe et al.,
2006; Bouchard et al., 2004; Carcea et al., 2010; Mann, Miranda, Weinl,
Harmer, & Holt, 2003; Moore et al., 2008; Piper, Salih, Weinl, Holt, &
Harris, 2005
). Thus, by directing exo- and endocytosis generally,
neurotrophin signaling may regulate the spatiotemporal organization of
receptors across the growth cone, and thus regulate growth cone sensitivity
to both neurotrophic and nonneurotrophic factors (
Leterrier et al., 2006
).
Evidence indicates that this is indeed the case for Trk receptors and
p75 in both intra- and interneuronal signaling
in vitro
and
in vivo
(
Majdan, Walsh, Aloyz, & Miller, 2001; Yoon, Casaccia-Bonnefil,
Carter, & Chao, 1998
). Moreover,
interpreting crosstalk between
different endosomal
signaling platforms
like TNF-
a
and NGF has
potential
implications
for disease pathophysiology as well
(
Takei &
Laskey, 2008
).
3.2. Cytoskeletal effector localization
How does signaling endosome localization influence actin remodeling in the
growth cone?
Growth cone morphology, physiology, and guidance are regulated
by spatiotemporal signal transduction across the growth cone that regulates
cytoskeletal dynamics. Proper signaling requires proteins to be appropriately
distributed, a task served by endosomal trafficking (
Winckler & Mellman,
2010
). Evidence from nonneuronal mammalian cells suggests that signaling
endosomes provide a physical platform for organizing, transporting, and
modifying the functions of signaling complexes and effectors regulating
cytoskeletal dynamics (
Disanza et al., 2009; Scita & Di Fiore, 2010
),
mechanisms that are also plausible in growth cones (
Fig. 2.4
). These
effectors include the Rho-family GTPases, Rho, Rac, and Cdc42
(
Lingwood & Simons, 2010
), which are key effectors linking extracellular
receptor
and CAM-mediated signals
to regulated actin dynamics
