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zone itself (Magdeleno et al., 2002). This misexpression
experiment basically generates a reelin sandwich.
Reelin is still expressed by the Cajal-Retzius cells, at
the superficial surface of the cerebral cortex, but in
these mice it is also expressed in the ventricular zone.
If reelin is a stop signal or an attractant, the migrating
neuroblasts should never leave the ventricular zone.
However, they found that the nestin-reelin mice were
essentially normal. The migrating neuroblasts still left
the ventricular zone on schedule and in fact made basi-
cally normal layers (Figure 3.29). Therefore, it is
unlikely that reelin acts as either a chemoattractant or
a stop signal. What then does this molecule do in the
process of cell migration? These authors found a clue
in a modification of this experiment. They mated the
nestin-reelin mice with reeler mice. These mice only
have the reelin in the ventricular zone and no longer
express any reelin in the Cajal-Retzius cells. Although
the cortical lamination was not perfect, it was
improved over that of the reeler mouse. As noted
above, reelin is also important for cerebellar Purkinje
cell migration and lamina formation, and the nestin-
reelin was even more effective in rescuing the cerebel-
lar phenotype of the reeler mouse. Therefore, it looks
as if it is less important where the reelin is localized in
the developing cortex and cerebellum, as long as there
is some reelin around.
In addition to reelin and astrotactin, a large number
of molecules have been implicated in neuroblast
migration in the cerebral and cerebellar cortices. Inte-
grins are cell adhesion molecules that allow many dif-
ferent types of cells to attach to the proteins in the
extracellular matrix. Since these adhesion receptors
are necessary for the pial extracellular matrix forma-
tion, it is not surprising that they are required for the
appropriate formation of the glial scaffold and hence
the migration of the neuroblasts and correct position-
ing of the cerebral cortical neurons. It is as if you were
trying to stand a ladder up without a wall to lean it
against. Another class of molecules, the neuregulins
and their receptors, likely has a very different role.
Neuregulin, or glial growth factor, activates receptor
tyrosine kinases called ErbBs (1-4) on the glial cell sur-
faces and promotes the appropriate differentiation
and/or survival of the glial cells. Without the glial
cells adopting their elongate morphology, the neurob-
last migration is abnormal. Again comparing this with
a ladder, it is as if you were trying to climb a ladder
made of rubber.
In sum, many cellular and molecular interactions
are necessary for proper arrangement of the neurons
in the complex neuronal structures that make up the
mature brain. Nearly all the neurons in the brain end
up some distance from where they were generated in
the ventricular zone, and the mature neuronal circuitry
depends on cells getting to the right place at the right
time. Mice with mutations in genes critical for neu-
ronal migration have motor deficits, but it is likely that
more subtle deficits are caused by less dramatic
changes in neuronal migration. Several inherited
mental retardation syndromes in humans are now
known to be caused by defective migration of cortical
neuroblasts. The beautiful choreography of neuronal
migration is clearly an essential part of building a
working nervous system.
A
Mouse brain,
sagittal section
B
Cajal-
Retzius
Cells
Migrating
neurons
Layer
V neurons
Radial
glia
wt
rl/rl
C
wt/nestin-reelin
rl/nestin-reelin
FIGURE 3.29 Is reelin a “stop” signal or a “go” signal? A trans-
genic mouse with reelin expressed in the wrong place might help
sort this out. A. Sagittal section through a mouse brain to show
where cortical sections are taken from. B. Mice with reelin expres-
sion under the control of the nestin promoter, and therefore
expressed in the ventricular zone, generate a reelin “sandwich” for
the migrating neurons. If reelin is a stop signal or an attractant, the
migrating neuroblasts might never leave the ventricular zone. Sur-
prisingly, the nestin-reelin mice had remarkably normal cortical lam-
ination. C. Mating nestin-reelin mice with reeler -deficient mice leaves
reelin only in the ventricular zone and no longer express in the Cajal-
Retzius cells. This actually improved the lamination over that
observed in the reelin-deficient mice. Therefore, it appears that it is
less important where the reelin is localized, as long as there is some
reelin around.
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