NEUROBIOLOGY: ON GENETIC CONTROL OF CORTICAL CONVOLUTIONS
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The following points are made by Pasko Rakic (Science 2004
303:1983):
1) The cerebral cortex is composed of a sheet of neurons that
during evolution has increased by three orders of magnitude in
surface area. In humans, the cerebral cortex has assumed a highly
convoluted (gyrencephalic) shape. A remarkable aspect of cortical
development is that none of the constituent neurons, even in the
large primate cerebrum, are generated within the cortex itself.
Rather, cortical neurons originate in the proliferative
ventricular and subventricular zones lining the cerebral cavity
and then migrate to their proper laminar and areal positions (1).
In all mammals, but particularly in the gyrencephalic primate
cerebrum, this migration to appropriate positions critically
depends on the transient scaffolding formed by shafts of
elongated radial glial cells that span the fetal cerebral wall
(2).
2) Elucidation of the cellular and molecular events underlying
cortical development has come primarily from investigating the
smooth (lysencephalic) mouse cerebrum, which is amenable to
experimental approaches including the induction of genetic
mutations (3-5). In contrast, spontaneous mutations in humans are
nature's unique experiments that enable deciphering of
developmental mechanisms, such as the formation of cortical
convolutions, that cannot be studied in lysencephalic rodents.
3) Piao et al (Science 2004 303:2033) have provided a state-of-
the-art genetic analysis of a human disorder called bilateral
frontoparietal polymicrogyria. Patients with this syndrome have
an enlarged number of smaller convolutions in the cerebral cortex
associated with profound cognitive abnormalities. Piao et al
(2004) report that abnormal development in the same cortical
location in these patients is caused by eight separate mutations
in the human GPR56 gene encoding an orphan G protein-coupled
receptor. This finding implicates G protein-coupled receptor
signaling in the development of specific areas of the human
cerebral cortex.
4) Bilateral frontoparietal polymicrogyria is an autosomal
recessive syndrome that has been mapped to a locus on chromosome
16q12-21. In the new study, Piao et al (2004) demonstrate that in
each of 12 pedigrees the GPR56 mutations segregate with
polymicrogyria, and only affected patients carry homozygous GPR56
mutations. They diagnosed the disease according to characteristic
cranial magnetic resonance imaging and clinical manifestations.
No mutations were observed in the GPR56 gene in 260 control
chromosomes.
References (abridged):
1. P. Rakic, Science 183, 425 (1974)
2. P. Rakic, Science 241, 170 (1988)
3. E. M. Miyashita-Lin et al., Science 285, 906 (1999)
4. J. L. Rubenstein, P. Rakic, Cereb. Cortex 9, 521 (1999)
5. K. M. Bishop et al., Science 288, 344 (2000)
Science http://www.sciencemag.org
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NEUROBIOLOGY: ON THE DEVELOPMENT OF THE CEREBRAL CORTEX
The following points are made by Pat Levitt (Science 2004
303:48):
1) Timing seems to be everything in the life of a progenitor
cell. There is a striking correlation between the time during
development when a cell is born (that is, when it exits the cell
cycle) and the type of mature cell that it will become. This
poses a special problem for the developing nervous system, which
is composed of diverse types of neurons and glial cells.
1) Timing seems to be everything in the life of a progenitor
cell. There is a striking correlation between the time during
development when a cell is born (that is, when it exits the cell
cycle) and the type of mature cell that it will become. This
poses a special problem for the developing nervous system, which
is composed of diverse types of neurons and glial cells. On page
56 of this issue, Hanashima et al. (1) determine how one
particular transcription factor, Foxg1, actively controls the
orderly production of different types of neurons in the mouse
cerebral cortex.
2) The mammalian cerebral cortex comprises six distinct layers;
the neurons of each layer are born at different times, exhibit
unique traits, and contribute to neuronal circuits that carry out
distinct functions. How is it, then, that early progenitor cells
produce neurons of a particular type, whereas later progenitors
generate other kinds of neurons that will end up in different
layers of the cortex? The molecular regulator of this process has
proved elusive, despite intensive investigation prompted by the
seminal transplant studies of McConnell and colleagues (2,3).
These investigators showed that late progenitors lose their
potential to produce early types of neurons, even when placed in
a temporally appropriate environment. A new study by Hanashima et
al (1) suggests that the apparent temporal restriction of
progenitor cell potential is an active process that involves
molecular suppression of an early intrinsic cell program by the
transcription factor Foxg1. If left unchecked, the progenitor
cell conceivably could produce the same type of neuron ad
infinitum, an interesting implication for the field of stem cell
biology.
3) Using cell type-specific and layer- specific markers,
Hanashima et al (1) analyzed the cerebral cortex of mice lacking
the Foxg1 gene. Their first observation was that the earliest
born neurons, called Cajal-Retzius (CR) neurons, of layer I were
grossly overrepresented. These CR neurons seem to have thrived at
the expense of ER81+ neurons of layers VI and V, which are
generated later. Under normal circumstances, Foxg1 is expressed
by progenitor cells and postmitotic neurons in the cortical
plate, but is completely down-regulated by CR neurons. Thus, the
progenitor cell pool seems to be committed to producing the
entire population of CR neurons before Foxg1 is expressed.
4) One can expect that future studies will determine the possible
limits on retention of early cell fate potential by later
progenitor cells. Is it possible that any progenitor cell, even
when isolated from the last stages of tissue formation, can
produce earlier born neurons in the absence of a suppressor? If
so, this may necessitate a modified definition of the multipotent
progenitor cell. And if one throws self-renewal into the mix,
neuroscientists may turn their attention toward identifying the
active molecular components of cell fate regulation and stem cell
differentiation that fall on both sides of the activation-
suppression dipole.(4,5)
References (abridged):
1. C. Hanashima, S. C. Li, L. Shen, E. Lai, G. Fishell, Science
303, 56 (2004)
2. S. K. McConnell, C. E. Kaznowski, Science 254, 282 (1991)
3. G. D. Frantz, S. K. McConnell, Neuron 17, 55 (1996) [Medline].
T. Isshiki, B. Pearson, S. Holbrook, C. Q. Doe, Cell 106, 511
(2001)
4. M. J. Belliveau, T. L. Young, C. L. Cepko, J. Neurosci. 20,
2247 (2000)
5. T. M. Jessell, Nature Rev. Genet. 1, 20 (2000) [Medline]. C.
M. William, Y. Tanabe, T. M. Jessell, Development 130, 1523
(2003)
Science http://www.sciencemag.org
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MICROCIRCUITRY IN THE CEREBRAL CORTEX
The cerebral cortex is a thin surface layering of nerve cells of
the brain, the region only several millimeters thick but
covering all of the brain surface. This is the part of the
central nervous system most intimately involved with the so-
called "higher faculties", although the cortex operates in
concert with other parts of the brain. The structure is primitive
in lower mammals, and is found progressively more pronounced and
with greater surface area in primates and man.
The following points are made by J. Kozloski et al (Science 2001
293:868):
1) The cortical microcircuit, i.e., the intra- and interlaminar
connections within a local neocortical region, is still largely
unknown, although its characterization is essential to any theory
of cortical function. The search for rules governing the cortical
microcircuit has revealed wide diversities of neurons, columnar
and horizontal connectivity, and distinct interlaminar and long-
range projections (output connections). Connections from other
cortical neurons can be precise, targeting specific postsynaptic
locations.
2) However, connectivity rules among excitatory cells, which
constitute the vast majority of cortical neurons, remain unclear.
Some studies indicate that excitatory neurons are weakly
interconnected in probabilistic patterns, so that specificity can
be found only at the statistical level. At the same time, because
the number of different classes of neocortical neurons is still
unknown and could approach several hundreds, any apparent lack of
target specificity might result from heterogeneous sampling.
Also, physiological studies indicate remarkable circuit
specificity.
3) The authors used an optical probing technique to detect
postsynaptic targets of neurons in brain slices, and then chose
targets for dual recordings. By imaging hundreds of neurons
simultaneously, while electrically stimulating a trigger cell,
the authors optically detected the "follower" neurons connected
to it. The authors suggest their data reveal precisely organized
microcircuits.
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