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| Pasko Rakic |
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Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA
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Presentation: |
| 2002-10-10, 09:00-09:30 |
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| Cortical development. |
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Why study development of the human cerebral cortex? Our experience has been that although the basic principles of cortical development in all mammalian species are remarkably similar, the modifications of developmental events during evolution produce not only quantitative (e.g. the number of neurons, timing and sequence of cellular events) but also qualitative changes (e.g. the elaboration of new neuronal types, pattern of connections and addition of functionally specialized areas). The small genetic differences between mammalian species are predominately expressed in the brain and usually act at the time of the progenitor's exit from the cell cycle. Our strategy has been to study developmental events in mouse, monkey and human embryos, as well as in mutant mouse models, both in vivo and in vitro.
I will describe several modifications of human cortical development that can often be traced to the action of philogenetically conserved genes generating an outcome that depends on the evolutionary new context. For example, we have found that the duration of the stem cell cycle is about 4 times longer in human than in rodents, which poses several logistical problems in constructing a large neocortex. There are also marked differences in timing of divergence of radial glial (RG) and neural stem cell lines as well as in the size, level of differentiation and longevity of RG in human. For example, in primates RG stop dividing and express GAFP while serving as a guide for migrating neurons in the large and convoluted cerebrum. The thousand-fold increase in cortical surface during evolution without a comparable increase in its thickness can be explained in the context of the radial unit hypothesis of cortical development. The timing of genesis, composition, and the ratios of programmed cell death in the subpial granular layer (SPG) in the marginal zone/layer I, suggest an expanded, diversified and more protracted role of this transient layer in primates. We also discovered distinct clones of GABAergic neurons in the human embryo that migrate from the ganglionic eminence (GE) to the thalamic association nuclei that are not present in rodents nor non-human primates. Importantly, GABAergic interneurons of the human neocortex have a dual origin. Using retroviral labeling in organotypic slice cultures of the embryonic human forebrain, we have identified a distinct lineage of neocortical GABAergic neurons that, unlike in rodents, originate from Mash1-expressing progenitors of the dorsal VZ/SVZ. The remaining Dlx1/2 positive, but Mash1 negative interneurons originate from the GE of the ventral forebrain. Our findings indicate that modifications in the expression pattern of transcription factors in the human forebrain may underlie species-specific programs for the generation of cortical interneurons that may be differentially affected in genetic and acquired neurological disorders associated with specific classes of neurons in human. Our working hypothesis is that these novel evolutionary traits may be vulnerable to genetic mutations and environmental insults implicated in disorders of higher brain functions ranging from autism and developmental dyslexia to Alzheimer's disease and Schizophrenia.
Selected references on human forebrain development:
- Rakic P & Sidman RL l968 Supravital DNA synthesis in the developing human and mouse brain. J Neuropath Exp Neurol 27: 246-276
- Sidman RL & Rakic P.l973 Neuronal migration with special reference to developing human brain: a review. Brain Res. 62: l-35
- Kostovic I & Rakic P 1990 Developmental history of the transient subplate zone in the macaque monkey and human brain. J Comp Neurol 297: 441-470
- Rakic P 1988 Specification of cerebral cortical areas. Science 241: 170?176
- Rakic P 1995 A small step for the cell - a giant leap for mankind: a hypothesis of neocortical expansion during evolution. Trends in Neuroscienc, 18: 383-388
- Kornack DR & Rakic P 1998 Changes in cell cycle kinetics during the development and evolution of primate neocortex. Proc Na. Acad Sci 95: 1242-1246
- Letinic K & Rakic P 2001 Telencephalic origin of human thalamic GABAergic neurons Nature Neurosc. 4: 931-936
- Zecevic N & Rakic P 2001 Development of layer I neurons in the primate cerebral cortex J Neurosc. 21: 5607-5619
- Letinic K, Zoncu, R & Rakic P 2002 Origin of GABAegic neurons in the human neocortex. Nature, 417: 645-649
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