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The growth cones of axons that cross the midline use the population of glial cells, at the
midline itself, as an important waypoint. If these cells are obliterated using the ricin toxin,
axons fail to cross the midline even though their distant targets are still present. 18 The midline
cells express the diffusible chemoattractants Netrin 1 and 2, and in the absence of these
molecules commissures fail to form properly, 19,20 being absent or much thinner than usual. 21
The receptor for Netrin, Frazzled (the homologue of the mammalian protein, DCC), is
expressed by, and required by, growth cones of axons destined to cross the commissures; 22
there is some evidence that Frazzled operates not as a conventional receptor but rather by pre-
senting netrins to other receptor molecules. 23
In frazzled mutant flies, axons typically fail to
cross the midline.
Attraction to the midline is a double-edged sword in promoting the crossing of the CNS by
commissural axons because, like any other waypoint, it creates a potential trap. Growth cones
attracted to netrin will never leave the midline unless their navigational preferences can be
changed on making contact with their midline waypoint. Some parts of the mechanism that
alter these preferences have now been identified.
As well as producing the chemoattracts Netrin 1 and 2, the midline cells express the diffus-
ible chemorepellant Slit. Slit signals through the receptor Robo, which antagonizes produc-
tion of protrusive leading edges. Growth cones of axons that are never meant to cross the
CNS express Robo and are sensitive to chemorepulsion so they stay away from the midline.
Mutations that block expression of functional Robo cause even these axons to cross. 24
Conversely, if Robo expression is engineered to be active even in what should be commis-
sural axons, these avoid crossing the midline. 25
Surprisingly, even neurons whose axons are destined to cross the CNS express Robo
protein. The transport of Robo to the membrane is, however, thwarted by the activity of
another protein called Comm (from the gene 'commissureless'), 26 which targets nascent
Robo peptide to the late endocytic pathway and destroys it. 17 Without Comm, Robo is
active and axons cannot cross the midline, preventing the formation of commissures. 26
Comm is inactivated when growth cones reach the midline, by a mechanism that is not
understood, so Robo becomes active and the midline is perceived as a repulsive place
( Figure 12.4 ); the growth cones therefore head away from it and are prevented from
crossing again. 27 If the expression of Robo is blocked, growth cones cannot perceive the
midline as repulsive even when they have crossed it, so they keep re-crossing in pointless
circles. 24
(This phenotype is how robo, an abbreviation for 'roundabout', acquired its
name.)
Although midline crossing shows several attributes of waypoint navigation, careful
analysis of mutants reveals that cells heading for their midline waypoint are capable of
detecting at least one subsequent waypoint too. The basic symmetry of metazoan bodies
means that most crossings from left to right have balancing crossings from right to left,
and most targets present on the left side are also present on the right side. When mutations
in the comm and netrin genes are used to block the formation of commissures, axons now
incapable of crossing to the contralateral side of the CNS frequently find their 'correct' targets
on the ipsilateral ) half of the CNS. 21,28
) Ipsilateral
ΒΌ
on the same side (as).
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