Biology Reference
In-Depth Information
2.2.1 Neurotrophins signaling
Neurotrophins are a family of trophic factors critical for neuronal survival
and development. In mammals, the neurotrophin family includes nerve
growth factor (NGF), brain-derived neurotrophic factor (BDNF),
neurotrophin-3 (NT-3), and NT-4/5. Cellular functions of neuro-
trophins are mediated by two classes of membrane-bound receptors:
the tropomyosin receptor kinase receptors (TrkA, TrkB, and TrkC)
and the low-affinity neurotrophin receptor p75. Neurotrophins such as
NGF, BDNF, and NT-3 are typically the most effective extrinsic signals
that stimulate axon growth in a diverse array of neuronal populations in
the CNS and PNS. The regulatory role of Cdk5 in neurotrophin signal-
ing was first revealed when suppression of Cdk5 activity was shown to
attenuate NGF-stimulated neurite outgrowth in PC12 cells (
Harada, Mor-
ooka, Ogawa, & Nishida, 2001
). Apart from NGF, Cdk5 also modulates
BDNF-induced dendrite outgrowth through phosphorylation of its cognate
receptor TrkB. Specifically, BDNF-induced activation of TrkB is associated
with elevated Cdk5 activity, presumably through phosphorylation of Cdk5
at Tyr15. Cdk5 then phosphorylates TrkB at Ser478, whose phosphoryla-
tion is required for BDNF-induced dendritic growth in primary hippocam-
pal neurons (
Cheung, Chin, Chen, Ng, & Ip, 2007
). Furthermore, a recent
study in our laboratory revealed the
in vivo
function of this serine phos-
phorylation in activity-dependent structural plasticity and spatial memory
(On et al., 2012). However, whether Cdk5 also plays a role in the regu-
lation of axon growth by BDNF/TrkB signaling is unclear.
Aside from axon growth during development, the central importance
of BDNF/TrkB signaling in axon regeneration is underscored by several
lines of evidence. First, even partial reduction of TrkB expression leads to
profound defects on axon regeneration. Mice with heterozygous muta-
tion in the
trkB
gene exhibited significantly reduced number of motor
neurons that regenerated axons after PNS injury (
Boyd & Gordon,
2001
), suggesting axon regeneration ability is highly sensitive to the dos-
age of
trkB
gene. Second, increased TrkB expression promotes axon re-
generation
in vivo
. Hollis and colleagues reported that overexpression of
TrkB enhances regeneration of corticospinal axon into subcortical lesion
sites after subcortical axotomy, whereas no regeneration was found in the
absence of TrkB overexpression (
Hollis, Jamshidi, Low, Blesch, &
Tuszynski, 2009
). Moreover, expression of BDNF and TrkB is induced
attheinjurysite(
Boyd & Gordon, 2001
). Given the critical roles
of BDNF/TrkB signaling in axon regeneration and regulation of TrkB
