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In addition to the use of in vitro systems for study-
ing migration, advances in our understanding of the
molecular mechanisms of cell migration have come
about by analysis of naturally occurring mouse muta-
tions that disrupt the normal migration of neurons.
One important function of the cerebellum is to main-
tain an animal's balance. Lesions to the cerebellum in
humans frequently produce a syndrome that includes
unsteady walking, known as ataxia. Genetic disrup-
tions of the cerebellum in mice produce a similar syn-
drome, and therefore they can be identified and
studied. By screening large numbers of mice for motor
abnormalities, several naturally occurring mutations
have been identified that disrupt cerebellar develop-
ment (Caviness and Rakic, 1978). Because of the nature
of the symptoms, these mutant mouse strains have
names like reeler , weaver , and staggerer . The mutant
genes that underlie these phenotypes have been
identified, and one of these mutants, reeler , has been
particularly informative in understanding neuronal
migration.
The reeler mutant mouse has ataxia and a tremor.
Histological examination of individually labeled
neurons in reeler mutant cerebral and cerebellar cortex
revealed gross malpositioning of the cells. In the cere-
bellar cortex, the Purkinje cells are reduced in number
and, instead of forming a single layer, are frequently
present as aggregates. There are fewer granule cells,
and most of them have failed to migrate below the
Purkinje cells (Figure 3.28). Thus, they lie external to
the Purkinje cells. In addition, many other regions of
the CNS, including the cerebral cortex, show similar
disruptions in normal cellular relationships. In the
cerebral cortex of the reeler mouse, instead of the
normal inside-out pattern, later generated neurons fail
to migrate past those generated earlier. Thus, these
mice have an outside-in organization.
The defective molecule underlying the reeler phe-
notype has been identified. It is a large glycoprotein,
named reelin , containing over 3000 amino acids, and it
bears similarities to some extracellular matrix proteins
(D'Arcangelo et al., 1995). The reelin protein is
expressed by the granule cells in the external granule
cell layer from the very earliest stages of development.
In the cerebral cortex reelin is expressed by the most
superficial neurons, the Cajal-Retzius cells. Several
additional mutant mice have been found to have reeler -
like disruptions in their cortical lamination and act in
the same molecular pathway as reelin. Mutations in
the genes coding for a tyrosine kinase called disabled,
LDLR8 and VLDLR (low and very low density
lipoprotein receptors), ApoE (apolipoprotein E, an
important factor in lipid transport), and cdk5 (a cyclin-
dependent protein kinase—see Cell-Cycle Box) all
cause defects in cerebral cortical neuroblast migration
similar to those found in reeler mice (Jossin et al., 2003).
In the reeler mice, the neuroblasts do not migrate past
the subplate cells, and they appear to migrate at
oblique angles rather than to track along the glial scaf-
fold. The LDLRs, along with ApoE, form a receptor
complex that phosphorylates the disabled protein
upon reelin binding. Once phosphorylated, disabled
can recruit other second messengers in the tyrosine
kinase pathway and activate a host of cellular
responses. The LDLRs and ApoE receptors are
expressed in the migrating neuroblasts and in the
radial glia themselves, while reelin is made by the
Cajal-Retzius cells at the cortical surface. The observed
cellular expression pattern of reelin and its receptors
has led to two basic classes of hypotheses for its func-
tion during cortical development: (1) reelin might be a
chemoattractant in cerebral cortex, causing the migrat-
ing neuroblasts to move toward the source of reelin in
the Cajal Retzius cells in the superficial layers of the
cortex; (2) alternatively, reelin could act as a stop signal
at the cortical surface, telling the neuroblasts to “get
off the track” and form a new cortical layer. In support
of the second hypothesis, Dulabon et al. (2000) have
found that adding reelin to migrating neuroblasts in
cell culture causes them to stop their migration.
However, this result is not inconsistent with reelin
playing a role as a chemoattractant, since adding reelin
to cell culture surrounds the migrating neuroblasts
with the potential attractant and thus causes them to
be attracted equally in all directions and to stop
moving. To distinguish between these two possibili-
ties, Curran's group generated a transgenic mouse that
has reelin expressed under the control of the nestin
promoter, and therefore expressed in the ventricular
Wild
type
Reeler
mutant
FIGURE 3.28 The reeler mutation in mice disrupts cerebellar
development. In normal mice, the Purkinje cells form a single layer
in the cortex. In reeler mice, the Purkinje cells do not migrate to the
cortex but remain in large aggregates. The other cerebellar neurons
are also malpositioned in the cerebellar cortex of the reeler mice. As
a result, the normal function of the cerebellum in controlling balance
is disrupted in the reeler mice, and so they “reel.”
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