Biology Reference
In-Depth Information
on the earlier ones having already established a pathway and, if these early axons are pre-
vented from growing, later ones fail as well.
34
The optic nerve is automatically structured
by this process so that its centre represents the centre of the retina and its periphery repre-
sents the periphery. In 'lower' vertebrates such as fish, retinal growth is continuous through
adult life and new axons keep being added to the optic nerve; in mammals, the process stops
during late foetal development.
The first navigational problem faced by the axonal growth cone produced by a newly
differentiated peripheral retinal ganglion cell is turning the right way to find the optic nerve.
They are probably aided in this by cells even further to the periphery that have not yet differ-
entiated to produce axons. These cells secrete large amounts of chondroitin sulphate proteo-
glycan,
35
which is known to be repulsive to a variety of growth cones.
36
e
38
Axons mistakenly
attempting to migrate centripetally will therefore be repelled and turned back towards the
centre of the retina, where the optic nerve is found.
Axons migrating towards the optic nerve migrate across scattered cells that express Slit1 and
many cells that express Slit2.
Ref
39
In many other contexts, such as control of midline crossing
described above, Slit proteins are repulsive, but in the retina they seem to be attractive to
growing axons: interfering with their production, by mutating a regulator of Slit1 expression
(only), inhibits the migration of retinal ganglion cell growth cones to the optic nerve
39
and those
that do penetrate the area fasciculate strongly, as if they nowprefer each other's company to any
other available substrate. Forcing some cells of the retina to express Slit1 strongly, using electro-
poration of an expression construct, causes axons to associate mainly with these cells. It is not
clear why Slit1 is attractive in the retina, although in other systems Slit proteins are cleaved
proteolytically
40
and N-terminal fragments of Slit proteins are attractive even when the whole
protein is repulsive.
41
Also, again in other systems, some extracellular matrix components or
cAMP can persuade cells to view fragments of Slit proteins as attractive rather than repulsive.
42
Together, these observations suggest that the scattered Slit1-expressing cells of the retina form
a pathway of attractivewaypoints leading towards the centre of the retina and the optic nerve. It
is possible that the Slit2 expressed by other cells remains repulsive, and that the opposing effects
of the two proteins help to confine the axons to their pathway.
The centrifugal sequence of retinal ganglion cell differentiation means that growth cones
from new cells heading towards the optic nerve will soon come across the axons already laid
down by cells older than themselves. Faced with the choice between continuing to migrate on
the Slit1-expressing cells or fasciculating with existing axons, growth cones tend to chose
fasciculation. This depends on specific adhesion molecules expressed on the axon surface.
The axons of retinal ganglion cells in the goldfish Carrassius auratus, for example, express
the adhesion molecules neuropilin and L1;
43
interfering with either of these molecules using
monoclonal antibodies interferes with normal guidance. Antibodies against L1 disrupt
fasciculation without preventing the axons eventually reaching the optic nerve while those
against neuropilin disrupt fasciculation and cause the axons to become seriously lost and
to wander about in pointless circles.
43,44
Similar results have been obtained using anti-L1
in rat retina.
45
L1 is not just an adhesion molecule; it is part of the Semaphorin 3A receptor
complex
46
and it is also a ligand for certain integrins,
47
so it can participate in several aspects
of signal transduction. The role of L1 in fasciculation in the retina may therefore be either by
direct adhesion or by modulation of responses to other factors by intracellular signalling,
or some combination of these effects.
