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3 H-thymidine
Pregnant female
Pial surface
Injected at E11
Injected at E13
Injected at E15
VZ
Cerebral cortex
Birth
Process tissue
Radial glial cell
CER
CTX
FIGURE 3.16 Migration of neurons along radial glia. The radial
glial fibers extend from the ventricular zone to the pial surface of the
cerebral cortex. A section through the cerebral cortex at an interme-
diate stage of histogenesis shows the relationship of the radial glia
and the migrating neurons. The postmitotic neurons wrap around
the radial glia on their migration from the ventricular zone to their
settling point in the cortical plate. (Modified from Rakic, 1972)
T
OB
SC
Autoradiography
E11
E13
E15
described above to first demonstrate the inside-out
pattern of cerebral cortical histogenesis. The neurons
labeled in the cortex of pups born from pregnant
female rats injected with thymidine on the 13th day of
gestation were located in the deeper layers of cortex,
whereas the neurons labeled after a thymidine injec-
tion on the 15th day of gestation were found more
superficially (Figure 3.17). This inside-out pattern of
cortical neurogenesis is conserved across mammalian
species. Figure 3.18 shows the results of similar thymi-
dine birthdating experiments in the monkey, where the
process of neurogenesis is much more prolonged than
in the rat. Thymidine injections at progressively later
stages of gestation result in progressively more super-
ficial layers of cerebral cortical neurons being labeled.
Each cortical layer has a relatively restricted period of
developmental time over which it is normally gener-
ated (Figure 3.18).
While the crawling of the neuroblast along the radial
glial scaffold has been well recognized for over 30
years, recent direct visualization of the process in
developing mouse cerebral cortex has yielded some
surprises. In these studies, the ventricular zone was
labeled using a dye that marked a subpopulation of the
newly generated neuroblasts. As these cells left the
ventricular zone, their leading processes were visible.
Time-lapse imaging of dye-labeled neuroblasts shows
clearly that many of the neuroblasts migrate just as pre-
dicted from the EM reconstructions of Rakic. However,
direct visualization of the migration process also
revealed that many of the neuroblasts move via a very
different process, a process termed somal translocation .
Thymidine-labeled neurons ( )
FIGURE 3.17 Birthdating studies demonstrate the inside-out
pattern of cerebral cortical histogenesis. Pregnant female rats are
given injections of 3H-thymidine at progressively later stages of ges-
tation. When the pups are born, they are allowed to survive to matu-
rity, and then their brains are processed to reveal the labeled cells.
Neurons that have become postmitotic on embryonic day 11 are
found primarily in the subplate (now in the subcortical white
matter), while neurons “born” on day E13 are found in deep corti-
cal layers, that is, V and VI, and neurons generated on E15 are found
in more superficial cortical layers, that is, IV, III, and II. The most
superficial layer, layer I, contains only the remnants of the preplate
neurons (not shown). (Modified from Angevine and Sidman, 1961)
The migrating cell has a leading process that extends to
the pial surface, while the cell body is still near the ven-
tricular zone at this early stage of cerebral cortical
development. Then, as the process gets progressively
shorter, it draws the cell soma to the pial layer as if it
were doing pull-ups on a bar (Nadarajah et al., 2001).
At the same time, other neuroblasts are migrating with
relatively constant leading processes, and presumably
these are more like those described from the EM recon-
structions. Some neuroblasts show both modes of
migration at different points in their path.
The direct visualization of neuronal migration gave
rise to another surprise. The relationship between the
radial glia and the progenitor cells has long been
thought to be separate. The glia were thought to be
 
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