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In addition to the information on cell cycle that has
been obtained from the use of H3-thymidine, it is also
possible to use this isotope to determine the precise
time points during embryogenesis when the neurons
and glia are generated—that is, become postmitotic.
While the progenitor cells are actively dividing,
they are synthesizing DNA and incorporate the 3 H-
thymidine. However, as noted above, since the thymi-
dine is available for only a few hours, progenitor cells
that continue to divide dilute their label over time. By
contrast, those cells that withdraw from the cycle and
become postmitotic soon after the 3 H-thymidine was
administered will remain heavily labeled with the
radioactive nucleotide. Thus, the postmitotic neurons
generated, or “born,” within a day after the 3 H-
thymidine injection will have heavily labeled nuclei,
and neurons generated later in development will be
more lightly labeled. Unlabeled cells are those that
withdrew from the cell cycle before the 3 H-thymidine
injection. This technique, pioneered by Richard
Sidman (1960), is known as thymidine “birthdating”
and has been applied to virtually all of the areas of the
developing mammalian nervous system (see Altman
and Bayer, 1985, for review).
The thymidine birthdating studies revealed that the
process of neurogenesis is remarkably well ordered.
In many areas of the developing brain, there are
spatial and temporal gradients of neuron production
(Figure 3.7). The generation of the cerebral cortex,
for example, proceeds from medial to lateral, and
the retina is generated in a central to peripheral direc-
tion. In general, there are well-conserved and orderly
sequences of generation of different types of neurons
and glia. For example, in the cerebral cortex, the
neurons are arranged in layers or lamina. During
neurogenesis, the different laminae are generated in
a sequence that is conserved from rats to monkeys.
Similarly, in the retina, there are six main types of
neurons and one type of glial cell, the Muller cell.
Thymidine birthdating of a wide variety of species has
shown that the various types of neurons are generated
in a well-conserved sequence, even though the period
of retinal histogenesis of a monkey takes place for
more than a month while that of a frog occurs in less
than two days.
Several additional generalizations can also be
derived from the large number of thymidine birthdat-
ing studies that have been carried out in the different
regions of the vertebrate CNS. As noted above, in many
areas of the developing CNS, distinct types of neurons
originate in a fairly invariant timetable. Often, the entire
population of one type of neuron, like the spinal
motoneurons, becomes postmitotic within a relatively
short period of development. In general, large neurons
3 H-thymidine
Pregnant female
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u
FIGURE 3.7 Complex gradients of time of origin of neurons in
the hippocampus. Detailed thymidine birthdating analysis of mouse
hippocampal formation shows the complex gradients in neuronal
production typical of the central nervous system. Pregnant mice
were given thymidine injections on the various days indicated
( E10-E18 ), and the brains of the pups born from these dams were
analyzed for labeled cells. Arrows indicate gradients in time. (Mod-
ified from Angevine, 1970)
are generated before small neurons in the same region.
For example, pyramidal cells become postmitotic be-
fore granule cells in the hippocampus, cerebral cortex,
and olfactory bulb, and in the cerebellum, Purkinje cells
are generated prior to granule cells (Jacobson, 1977).
Interestingly, it appears that the patterns of neuronal
generation are also consistent with the hypothesis that
phylogenetically older parts of the brain develop before
the more recently evolved structures.
CELL-CYCLE GENES CONTROL THE
NUMBER OF NEURONS GENERATED
DURING DEVELOPMENT
The factors that control the number of divisions in
both the vertebrate and invertebrate nervous systems
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