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and the ER (
Butowt & von Bartheld, 2005; Schwab, 1977
)andexistaseither
single lumen vesicles (
Altick et al., 2009
) or rarely inMVBs (
Altick et al., 2009
)
and lysosomes (
Claude, Hawrot, Dunis, & Campenot, 1982; Schwab, 1977
).
This complexity may reflect not only the heterogeneity of endosomal
populations but also crosstalk between Trk and p75 neurotrophin receptors,
which differ with respect to their signaling, endocytosis, and transport
through similar (
Bronfman, Tcherpakov, Jovin, & Fainzilber, 2003;
Hibbert, Kramer, Miller, & Kaplan, 2006
) and different (
Deinhardt et al.,
2006
) endosome populations. Together these data argue that current
models on signaling endosome biology are oversimplified and incomplete.
2.4. Signaling endosomes and intra-axonal translation
Supporting the argument that signaling endosome models are incomplete,
recent studies show that signaling endosomes influence nuclear transcription
by effecting transcription factor translation locally in the axon. The classical
view of signaling endosome-nuclear signaling postulates that signaling
endosomes transport signaling molecules to the nucleus to affect transcrip-
tion factor activity. In recent studies, in compartmentalized DRG cultures,
however, applying NGF to distal neurites stimulated intraaxonal translation
of CREB and the subsequent retrograde transport of CREB to the nucleus
by TrkA signaling endosomes (
Cox, Hengst, Gurskaya, Lukyanov, &
Jaffrey, 2008
). Similarly, BDNF can stimulate intraaxonal translation of
SMAD1
/
5
/
8
transcripts. Interestingly, axon-derived SMAD1/5/8 was then
retrogradely transported by bone morphogenic protein-4 (BMP-4) signaling
endosomes to the soma, where SMAD1/5/8 was phosphorylated to a tran-
scriptionally active form, indicating that cooperative interendosomal signal-
ing between BDNF and BMP-4 can generate a retrograde signal that alters
transcription (
Ji & Jaffrey, 2012
). Thus, signaling endosomes may not need
to be transported retrogradely to effect transcription, or they may employ
both endosomal and nonendosomal-dependent signaling. Local translation
in growth cones is well established (
Lin & Holt, 2007
) and is necessary for
growth cone steering in some cases (
Lin & Holt, 2008
). These findings
suggest the potential that signaling endosomes in growth cones could
also regulate the local translation of proteins necessary for growth cone
activities.
The idea that neurotrophin signaling can regulate the translation of pro-
teins that can locally regulate growth cone activities is supported by two
studies on like LIM kinase-1 (LIMK1), which can locally regulate actin
dynamics, LIM kinase-1. First, BDNF promoted actin polymerization
