Brain Development
113
inside to the outside, being the very re-
verse of tree ring formation, in that, newly
generated neurons stop their migration at
the marginal zone so as to get over the
predominated old neurons in the cortical
plate. A series of mutant mice exist that
have apparent phenotypes in layer forma-
tion; for example, the
reeler
mutation is
known to affect the order of layers in that
newly generated neurons cannot get over
the old ones in the cortical layer and so stay
inside the prepopulated cell layer, similar
to the formation of a tree ring, and ulti-
mately resulting in the reversed order of
theco
r
t
ica
llaye
r
s
.Thegenerespon
s
ib
le
for this phenotype encodes a large extra-
cellular protein named
Reelin
,wh
i
chi
s
secreted by the Cajal–Retzius (CR) cells in
the preplate. CR cells are thought to orig-
inate from the telencephalic ventricular
zone and are the Frst to reach the cerebral
marginal zone to form the preplate. The
role of CR cells in layer formation is signif-
icant because the secreted Reelin protein
appears to promote neuronal cell migra-
tion from the ventricular to the marginal
zone in order to get over the prepopu-
lated layer of cells. The Reelin receptor
is thought to be a molecular complex. A
component is the LDL receptor family,
namely, the very-low-density lipoprotein
receptor (VLDLR) and the apolipoprotein E
receptor type 2 (ApoER2) expressed by the
migrating cortical neurons. The cytoplas-
mic region of these receptors can interact
with an adapter protein Disabled (Dab-1),
and Reelin binding to the receptor com-
plex has been shown to induce tyrosine
phosphorylation of Dab-1. Double knock-
out mice for both receptor genes as well
as Dab-1 mutant mice (
Scrambler
or
Yotari
mice) resulted in the reeler phenotype,
indicating that these genes constitute the
main complex to regulate the neuronal mi-
gration and form the normal cortical layer
organization in a Reelin dependent man-
ner. Importantly, alpha3beta1 integrin,
expressed by migrating neurons was also
demonstrated to be able to bind to Reelin
and regulate the interaction between radial
glial Fbers and migrating neurons
in vitro
as well as
in vivo
.Geneknockou
to
fth
is
integrin resulted in reduction of the Dab-
1 protein level, suggesting that integrin
mediated cell adhesion might play a role
in the radial glial Fber guided neuronal
migration. The Reelin-Dab1 regulated cell
migration machinery has further been
shown to be required for the layer for-
mation in other tissues including the
cerebellum and hippocampus. In reeler
mutant mice, for instance, the Purkinje
cell layer was totally disorganized, and the
cell arrangement in the dentate gyrus of
the hippocampus was also perturbed, al-
though cell type differentiation
per se
was
not affected. This implicates Reelin-Dab1
regulated cell migration in the common
role of layer formation during develop-
ment and evolution.
5
Cellular Aspects to Wire up the Nerve Cells
into Functional Circuits
Once the nervous system is patterned and
unique sets of neurons are generated, they
must be connected to each other to con-
stitute functional neuronal circuits. In this
process, neurons should precisely send ax-
ons into remote target positions. Although
Ramon y Cajal had already suggested pos-
sible mechanisms explaining axon guid-
ance in the early 1880s, experimental
supports had been relatively poor for sev-
eral decades after him. In the 1950s, Sperry
rotated an eye in an adult newt by 180
,and
made the eye–tectum connections regen-
erate. He then demonstrated that the axons
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