|
ScienceWeek
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.
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
--------------------------------
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.
Science http://www.sciencemag.org
--------------------------------
ASSESSMENT OF THE DEVELOPMENTAL TOTIPOTENCY OF NEURAL CELLS IN THE CEREBRAL CORTEX OF MOUSE EMBRYO BY NUCLEAR TRANSFER
The following points are made by Y. Yamazaki et al (Proc. Nat. Acad. Sci. 2001 98:14022):
1) Animal cloning has been achieved for many years by transferring the nucleus of a somatic embryonic or fetal cell into an enucleated oocyte (1). Successful cloning by using adult somatic cells first was reported in the sheep (2), then in mice (3), cattle (4-5), goats, and pigs. The cloning technique is a very powerful tool to analyze the developmental potentials and genomic status of various somatic cell nuclei.
2) Site-specific DNA rearrangement in developing lymphocytes of the immune system is largely responsible for generating the highly diverse array of immunoglobulins and T cell receptors. Whereas neurons do not proliferate, there are superficial similarities between the immune system and the central nervous system. Extreme complexity, the capacity for memory, and extensive apoptosis during development are examples. These similarities have led to the hypothesis that the central nervous system and the immune system use similar somatic DNA rearrangement strategies during their development. The rearrangement activating gene, RAG-1 in the immune system also was detected in the central nervous system. Furthermore, knockout mice lacking DNA-repair enzymes DNA ligase IV and XRCC4 failed to repair DNA double-stranded breaks, causing defects in the immune system, and had gross cell death along neural differentiation in the embryonic cortex. It has been suggested recently that DNA rearrangement may play a role in neural cell development.
3) In summary: When neural cells were collected from the entire cerebral cortex of developing mouse fetuses (15.5-17.5 days post-coitum) and their nuclei were transferred into enucleated oocytes, 5.5% of the reconstructed oocytes developed into normal offspring. This success rate was the highest among all previous mouse cloning experiments that used somatic cells. Forty-four percent of live embryos at 10.5 days post-coitum were morphologically normal when premature and early-postmitotic neural cells from the ventricular side of the cortex were used. In contrast, the majority (95%) of embryos were morphologically abnormal (including structural abnormalities in the neural tube) when postmitotic-differentiated neurons from the pial side of the cortex were used for cloning. Whereas 4.3% of embryos cloned with ventricular-side cells developed into healthy offspring, only 0.5% of those cloned with differentiated neurons in the pial side did so. The authors suggest these facts seem to indicate that the nuclei of neural cells in advanced stages of differentiation had lost their developmental totipotency. The underlying mechanism for this developmental limitation could be somatic DNA rearrangements in differentiating neural cells.
References (abridged):
1. DiBerardino, M. A. (1997) Genomic Potential of Differentiated Cells (Columbia Univ. Press, New York), pp. 180-213.
2. Campbell, K. H. S. , McWhir, J. , Ritchie, W. A. & Wilmut, I. (1996) Nature (London) 380, 64-66.
3. Wakayama, T. , Perry, A. C. F. , Zuccotti, M. , Johnson, K. R. & Yanagimachi, R. (1998) Nature (London) 394, 369-374.
4. Kato, Y. , Tani, T. , Sotomaru, Y. , Kurokawa, K. , Kato, J. , Doguchi, H. , Yasue, H. & Tsunoda, Y. (1998) Science 282, 2095-2098.
5. Cibelli, J. B. , Stice, S. L. , Golueke, P. , Kane, J. J. , Blackwell, C. , Ponce de Leon, F. A. & Robl, J. M. (1998) Science 280, 1256-1258.
Proc. Nat. Acad. Sci. http://www.pnas.org
ScienceWeek http://scienceweek.com
|