Biology Reference
In-Depth Information
kinesin-1 to the future axon occurs even before morphological polarization
has taken place (
Hoogenraad & Bradke, 2009; Witte, Neukirchen, &
Bradke, 2008
). Microtubules in the axon are primarily stabilized by post-
translational modifications such as detyrosination and acetylation, and
kinesin-1 preferentially recognizes each of these modifications resulting in
selective translocation to axons (
Dunn et al., 2008; Konishi & Setou,
2009; Reed et al., 2006
). In polarized neurons, however, acetylation alone
is not sufficient to direct kinesin-1 to axons, and therefore axonal targeting
of kinesin-1 is thought to involve multiple posttranslational modifications
(
Hammond et al., 2010
). There are therefore a number of potential targets
at the AIS that could be manipulated to increase axonal localization of pro-
teins; however, it may be difficult to identify specific approaches that do not
interfere with the normal function of the cell.
3.2. Trafficking mechanisms within the axon
There is evidence that membrane proteins can be targeted to the axon by all
three of the routes discussed above, with
b
APP reportedly trafficking via
direct polarized trafficking (
Nakata & Hirokawa, 2003
) and the K(
þ
)-
dependent Na(
) exchanger (NCKX) trafficking via selective
endocytosis (
Lee et al., 2012
); however, there is perhaps the most evidence
for polarization via transcytosis, with studies reporting that
b
1 integrins (
Eva
et al., 2010
), TrkA (
Ascano, Richmond, Borden, & Kuruvilla, 2009
),
L1/NgCAM (
Wisco et al., 2003
), Caspr2 (
Bel, Oguievetskaia, Pitaval,
Goutebroze, & Faivre-Sarrailh, 2009
), and the cannabinoid type 1 receptor
(
Leterrier et al., 2006
) all traffic this way. The most heavily investigated
protein that traffics via transcytosis is the axonal adhesion molecule,
L1/NgCAM. Newly synthesized L1/NgCAM first appears on dendritic
surfaces, before appearing on the axonal surface (
Wisco et al., 2003
). Sub-
sequent studies revealed that L1/NgCAM initially traffics via NEEP21, a
neuron-specific endosomal protein which is restricted to the soma-
todendritic domain (
Yap, Wisco, et al., 2008
), and then traffics toward
the axon through early endosomes regulated by EHD1/EHD4 (
Lasiecka,
Yap, Caplan, & Winckler, 2010
). L1/NgCAM trafficking into dendrites
is mediated by a YRSLE endocytosis motif (
Yap, Nokes, et al., 2008
),
and axonal targeting is mediated by two sequences: a 15-amino acid glycine
and serine-rich region in the cytoplasmic domain, and an extracellular do-
main containing fibronectin type III-like repeats (
Sampo, Kaech, Kunz, &
Banker, 2003; Yap, Nokes, et al., 2008
). We have not identified these
þ
)/Ca(2
þ
