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still present. The suspicion that wunen is involved in repulsive signalling is confirmed by the
observation that forcing expression of wunen in a tissue normally permissive for germ cell
migration keeps that tissue germ cell-free.
10
Wunen proteins are expressed on the cell
membrane but they are, at least by homology, phosphatidic acid phosphatases with their
catalytic domains outside the cell. The molecular target of the wunens has not been identified,
but it is generally assumed that they work either by converting a phospholipid into a repul-
sive signal or by destroying a phospholipid necessary for cell surfaces to permit germ cell
migration.
10
As long as wunen expression is normal, primordial germ cells will migrate across
the gut surface in the right direction and to the right local destination even if their ultimate
destination, the gonad-forming mesoderm, is absent.
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e
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Once they have completed their migration across the surface of the gut, the primordial
germ cells leave it and enter the mesoderm where they split into two streams to colonize
the gonads, one on each side of the body. This phase depends on the expression of an enzyme,
HMGCoA reductase, by the somatic cells of the gonad.
13
Forcing the expression of HMGCoA
in other tissues makes these tissues attractive to primordial germ cells as well, suggesting
that the enzyme is involved in making a chemotactic signal. In mammals, HMGCoA is
important in the synthesis of cholesterol and a number of other small compounds. Choles-
terol cannot itself be the molecule involved in D. melanogaster because this species lacks
homologues of other mammalian enzymes essential for using the HMGCoA pathway for
cholesterol biosynthesis, but there is genetic evidence that farnesyl-diphosphate synthase
and geranylgeranyl-diphosphate synthase are required downstream of HMGCoA for germ
cell migration.
14
These enzymes are involved in the synthesis of isoprenoids, suggesting
that the still-unidentified chemoattractant is an isoprenylated protein. Pharmacological
evidence suggests that vertebrates, too, use HMGCoA and isoprenylated proteins to attract
primordial germ cells to their gonads.
15
Once in the gonads, germ cells form tight associa-
tions with somatic cells and begin the morphogenesis of the mature organ.
The reason for considering the migration of primordial cells to be an example of waypoint
navigation is not simply the fact that it proceeds by a series of discrete phases. Rather, it is
because absence of the final destination does not prevent the cells beginning even the active
part of their journey normally. They cross the gut normally even in mutants in which the
wunen-based guidance system of the next part of their journey is missing, and in flies with
normal wunen cues they navigate the gut surface normally even when there is no prospective
gonad to invade at the end of their journey.
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e
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They cannot, however, complete normal
journeys if any of the intermediate navigation systems are missing, even when the final
destination is intact and normal.
WAYPOINT NAVIGATION BY GROWTH CONE
S
Peripheral axons of insect nervous systems often make sharp turns as they navigate from
the cell body, in the tissues, to the CNS. In developing grasshopper prothoracic legs, an early-
migrating axon from the cell body of a neuron called Ti1, near the end of the leg, grows in
a stereotyped series of straight lines. The corners of these lines coincide with a set of large
and easily identifiable immature neuron cell bodies called F1, F2 and CT1 (
Figure 12.2
).
The CT1 cell, in particular, is associated with a very sharp turn. This course naturally
