Signaling Endosomes and Growth Cone Motility in Axon Regeneration - International Review of Neurobiology - page 53

regulated by gradients of intracellular signalingmolecules initiated by polarized
receptor activation at the plasma membrane ( Tojima, Hines, Henley, &
Kamiguchi, 2011 ). Neurotrophin signaling can generate intracellular
gradients of second messengers, including cAMP, cGMP, and Ca 2 þ , that
can steer growth cones ( Henley & Poo, 2004; Mai, Fok, Gao, Zhang, &
Poo, 2009; Nishiyama et al., 2003; Song, Ming, & Poo, 1997 ). Local
application of second messengers, like cAMP ( Lohof, Quillan, Dan, & Poo,
1992 ) and substrate-bound BDNF ( Maietal.,2009 ), are sufficient to turn
growth cones in vitro , arguing that neurotrophin signaling at the plasma
membrane is sufficient to turn growth cones and that neurotrophin-
generated signaling endosomes may be unnecessary for directed growth
cone motility at least in vitro .
However, data suggests signaling endosome formation is required for
neurotrophin mediated guidance in vivo . Migrating granule cell precursors
(GCPs) require a gradient of BDNF to correctly orient and migrate in
the developing cerebellum and BDNF-induced endocytosis of TrkB recep-
tors into endosomes is required. Moreover, correct migration depends on
TrkB-dependent secretion of BDNF by GCPs and the subsequent accumu-
lation of activated TrkB receptors in endosomes located in or adjacent to the
leading process, suggesting that a locally generated endosomal feedback loop
locally and critically potentiates neurotrophin signaling ( Zhou et al., 2007 )
to direct motility.
Feedback loops have been described in other systems ( Cheng et al.,
2011 ), further arguing that local signaling endosome signaling regulates neu-
rotrophin directed motility. For instance, NGF signaling enhances NGF
sensitivity by a positive feedback loop that locally increases levels of TrkA.
In compartmentalized sympathetic neurons, NGF stimulation increases
TrkA receptor numbers locally by a mechanism termed transcytosis. Upon
NGF stimulation, TrkA receptors are endocytosed at the soma, transported
anterogradely by Rab11 recycling endosomes to the axon terminals, and
then reinserted into the plasma membrane, locally increasing TrkA receptor
density ( Ascano, Richmond, Borden, & Kuruvilla, 2009 ), potentially in-
creasing both the magnitude and the duration of NGF signaling. A similar
mechanism may also regulate chemotropic turning in response to BDNF in
growth cones since applying BDNF to hippocampal neurons recruits TrkB
into distal axons via a Slp1/Rab27B/CRMP-2 complex directly linking
TrkB endosomes to kinesin-1 ( Arimura et al., 2009 ). In vivo , target-derived
NGF initiates a positive feedback loop by inducing the expression of TrkA
receptors, enhancing the magnitude and duration of prosurvival signaling