Biology Reference
In-Depth Information
FIGURE 11.10
Collapse of growth cones in culture elicited by treatment with repulsive molecules from the
posterior half-somite.
detail in Chapter 12). The optic tectum expresses a number of guidance molecules, amongst
which is the glycosylphosphatidylinositol (GPI)-linked membrane protein, Ephrin-A5 (syno-
nyms; AL1/ RAGS). This molecule is expressed in a gradient in the tectum, being strongest in
the posterior and weakest in the anterior.
51
The growth cones that grow into the tectum from
the eye, to lay down axons that will eventually carry visual information, express at least five
different receptors for Ephrin-A5;
52,53
these are EphA3, EphA4, EphA5, EphA6 and EphA7.
)
Interfering with the expression of Ephrin-A5, either by overexpression or mutation, causes
retinal axons to lose their way, to fail to produce a proper retinotectal map and in some cases
to end up in the wrong part of the brain altogether.
54,55
Simple culture experiments, in which growing axons are challenged with exogenously
applied Ephrin-A5, show that the molecule is a powerful inhibitor of axon elongation: contact
with it causes growth cones to 'collapse' so that they lose their fanned-out appearance and
dwindle to a blunt-ended axon
51
(
Figure 11.10
). This collapse is mediated by a signal trans-
duction system that interferes directly with cell locomotion. The receptor EphA4 interacts
directly with a guanidine nucleotide exchange factor (GEF) called Ephexin. Ephexin has
the ability to activate small GTPases of the Rho family by exchanging their GDP for GTP,
but its substrate specificity is altered by binding to activated EphA4. When no Ephrin-A is
bound by EphA4, Ephexin activates Rac and cdc42, each of which encourages leading
edge protrusion (see Chapter 8). When EphA4 binds an Ephrin-A ligand, though, Ephexin
stongly activates Rho, leading to the formation of myosin-associated stress fibres, and it no
longer activates Rac and cdc42.
56
The importance of this pathway is illustrated by the fact
that loading neurons with an inhibitor of Rho, such as the bacterial enzyme C-3 transferase,
or by inhibiting the Rho's downstream effector, the Rho-assocated kinase ROCK, renders
them relatively insensitive to Ephrin-As.
57
Together, these results suggest that inhibitory
Ephrins cause growth cone collapse by switching the organization of actin from that
)
Please note that Eph is
NOT
an abbreviation for 'Ephrin'; Ephrins and Ephs are two distinct families of
receptors, members of each family being ligands for certain members of the other family. The natural, but
incorrect, assumption that one name is just an abbreviation of the other is a frequent source of confusion.
