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transport within, into, and out of the growth cone. In late signaling endo-
somes, Rab7 can bind to the dynactin subunit p150 (Glued) in
dynein-dynactin motors via Rab7-interacting lysosomal protein and the
oxysterol-binding protein (ORP1L) (
Johansson et al., 2007
). ORP1L's
conformation is influenced by cholesterol concentrations and thus can act
as a cholesterol sensor (
Rocha et al., 2009
). Cholesterol concentrations
can influence close contacts between the ER and Rab7 signaling endosomes
which in turn controls the association of Rab7 endosomes with
dynein-dynactin motors, influencing their direction of transport and thus
their positioning in cells. Under low cholesterol conditions, ORP1L's
conformation induces the formation of ER-endosome contact sites and
the endosomes move toward microtubule plus ends, anterograde in axons.
Under high cholesterol conditions, this process is prevented, and Rab7
endosomes accumulate at microtubule minus ends as the result of
dynein-dynactin motor activity (
Rocha et al., 2009
). These studies indicate
the intricacy with which endosome transport can be regulated and suggest a
plausible mechanism whereby signaling endosomes harboring high choles-
terol lipid rafts are retrogradely transported out of the growth cone, whereas
nonlipid raft complexes may be endocytosed and shuttled down a different
endosomal pathway and possibly retained in the growth cone to regulate sig-
naling locally, or to be recycled or degraded. Whether these mechanisms
influence signaling endosome localization and signaling in growth cones
remains to be determined. Nevertheless, these results highlight the necessity
to understand the relationships between signaling endosome composition
and their relationships with other organelles. Increased cholesterol has
recently been implicated in altering endocytic trafficking and processing
of amyloid precursor protein in Alzheimer's disease (
Malnar et al., 2012
),
highlighting the need to understand endosomal trafficking and lipid compo-
sition for disease.
Trk receptor signaling may also alter the lipid environment of the signal-
ing endosome itself by recruiting signaling molecules that modify lipids.
Activated Trk receptors can locally activate both PLC
g
and PI3-K. Phos-
pholipid signaling through the PI3-K pathway is critical to TrkB activity
stimulated by BDNF during cerebellar precursor chemotaxis
in vivo
(
Zhou et al., 2007
), perhaps by differentially regulating Rab5 effectors.
In nonneuronal cells, the Rab5 effectors EEA1 and APPL1 and APPL2
compete for the same Rab5-binding site (
Schenck et al., 2008
) (e.g.,
Fig. 2.3A
). Depleting phosphatidylinositol-3-phosphate promotes Rab5-
APPL positive endosomes, resulting in enhanced growth factor signaling
