Biology Reference
In-Depth Information
downstream. Despite normal development of L1 positive axons in ankyrin
B
null
mice, L1 is lost unusually early in postnatal life. This is followed by catastrophic
axon swelling and degeneration of the entire optic nerve within the space of
2 weeks (Scotland
, 1998). Ankyrin
B
seems to have an essential role in
stabilizing L1 and linking the membrane to the actin cytoskeleton to provide
mechanical strength.
In myelinated axons, gangliosides appear to play a similar role. Gang-
liosides are glycosphingolipids in the axolemma that function as membrane-
anchored ligands for myelin-associated glycoprotein (Mag), a glycoprotein
located on adaxonal membranes of myelin-producing cells in CNS and PNS
that is also required for axon survival (Nguyen
et al.
, 1998). Mice
lacking the complex ganglioside synthetic protein Galgt1 develop progressive
axon degeneration in peripheral nerves and dorsal column of the spinal cord
(Chiavegatto
et al.
, 2009; Yin
et al.
, 2005). A more severe phenotype develops in
mice also lacking Siat9, which are unable to synthesize simple gangliosides too
(Yamashita
et al.
, 2000; Pan
et al.
, 2005).
Thus, another function of anterograde axonal transport important for
axon survival is to deliver these enzymes or their products into axons, in order to
maintain axon-glia interactions.
et al.
IX. LIFE AFTER (CELL) DEATH: THE WLD
S
PHENOTYPE
To return to a topic introduced at the beginning, it is interesting to reexamine
the delayed Wallerian degeneration in Wld
S
mice in the light of the discussions
above. Recent advances in understanding the Wld
S
mechanism are summarized
elsewhere (Coleman and Freeman, 2010), but an important new point emerges
here. Axon injury or cell death (Deckwerth and Johnson, 1994) interrupts the
supply of all cargoes from the cell body. Some will be essential, some nonessen-
tial. Some will have shorter half-lives than others, and some will be locally
synthesized in the distal axon stump. Among the essential missing factors,
Nmnat2 seems to have a key role in triggering Wallerian degeneration when
its level falls below a threshold needed for survival (Gilley and Coleman, 2010;
see above). This may explain why injured axon stumps degenerate after a latent
phase of around 36 h (Beirowski
, 2005; Lubinska, 1977). Delaying this
degenerative mechanism by substituting Nmnat2 with Wld
S
allows axons sur-
vive for 2-3 weeks, indicating that axons do not need replenishment of most
cargoes on this timescale. Thus, any protein whose loss triggers degeneration in
36 h should have a half-life that is a clear outlier from the population of essential
axonal proteins. Moreover, to preserve injured or transport-impaired axons even
longer, it would be useful to identify the next most labile, essential cargoes.
et al.
