Vulnerable periods during the development of the nervous system are sensitive to environmental insults because they are dependent on the temporal and regional emergence of critical developmental processes (i.e., proliferation, migration, differentiation, synaptogenesis, myelination, and apoptosis). Evidence from numerous sources demonstrates that neural development extends from the embryonic period through adolescence. In general, the sequence of events is comparable among species, although the time scales are considerably different. Developmental exposure of animals or humans to numerous agents (e.g., X-ray irradiation, methylazoxymethanol, ethanol, lead, methyl mercury, or chlorpyrifos) demonstrates that interference with one or more of these developmental processes can lead to developmental neurotoxicity. Different behavioral domains (e.g., sensory, motor, and various cognitive functions) are subserved by different brain areas. Although there are important differences between the rodent and human brain, analogous structures can be identified. Moreover, the ontogeny of specific behaviors can be used to draw inferences regarding the maturation of specific brain structures or neural circuits in rodents and primates, including humans. Furthermore, various clinical disorders in humans (e.g., schizophrenia, dyslexia, epilepsy, and autism) may also be the result of interference with normal ontogeny of developmental processes in the nervous system. Of critical concern is the possibility that developmental exposure to neurotoxicants may result in an acceleration of age-related decline in function. This concern is compounded by the fact that developmental neurotoxicity that results in small effects can have a profound societal impact when amortized across the entire population and across the life span of humans.

Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models.

Glial cells were long considered end products of neural differentiation, specialized supportive cells with an origin very different from that of neurons. New studies have shown that some glial cells—radial glia (RG) in development and specific subpopulations of astrocytes in adult mammals—function as primary progenitors or neural stem cells (NSCs). This is a fundamental departure from classical views separating neuronal and glial lineages early in development. Direct visualization of the behavior of NSCs and lineage-tracing studies reveal how neuronal lineages emerge. In development and in the adult brain, many neurons and glial cells are not the direct progeny of NSCs, but instead originate from transit amplifying, or intermediate, progenitor cells (IPCs). Within NSCs and IPCs, genetic programs unfold for generating the extraordinary diversity of cell types in the central nervous system. The timing in development and location of NSCs, a property tightly linked to their neuroepithelial origin, appear to be the key determinants of the types of neurons generated. Identification of NSCs and IPCs is critical to understand brain development and adult neurogenesis and to develop new strategies for brain repair.

The glial nature of embryonic and adult neural stem cells

Golgi and electronmicroscopic methods were used to define the shapes and intercellular relationships of cells migrating from their sites of origin near the ventricular surface across the intermediate zone to the superficial neocortical layers of the parietooccipital region in the brains of 75- to 97-day monkey fetuses. After mitotic division in either ventricular or subventricular zones, the cells enter the intermediate zone and assume an elongated bipolar form oriented toward the cortical plate. The leading processes, 50 to 70 μ long, are irregular cytoplasmic cylinders containing prominent Golgi apparatus, mitochondria, microtubules, ribosomal rosettes, immature endoplasmic reticulum and occasional centrioles. They usually terminate in several attenuated expansions, the longest one oriented toward the cortical plate. The trailing processes are more slender, relatively uniform in caliber and display few organelles.

Throughout the 3500 μ pathway across the intermediate zone the migrating cells are apposed to elongated, radially oriented, immature glial processes which span the full thickness of the cerebral wall. Most of the perikarya of these glial cells in the younger specimens lie in the ventricular or subventricular zones, but in older fetuses of this series many are found in the intermediate zone. The main characteristics of these fibers are: elongated cylindrical form contaiing numerous microtubules; electronlucent cytoplasmic matrix; short lamellate expansions protruding at right angles from the segment of the fiber which runs through the intermediate zone; and terminal endfeet joined at the pial surface to form a continuous sheet coated externally with basement membrane. It is suggested that glial radial fibers provide guidelines for cell migration through the complex mixture of closely packed cell processes and cell bodies that compose the developing cerebral wall. Strong surface affinity between radial fiber and migrating cell is suggested in regions where both follow precisely the same curving course from subventricular to intermediate zones and also in areas where large extracellular spaces separate other cells and processes but in which migrating cells and radial fibers remain closely paired nonetheless. Specific affinity between them is implied in the failure of migrating cells to follow any of the myriad differently-oriented processes they encounter. Several generations of postmitotic cells appear to migrate along the same radial fiber, a developmental mechanism that would allow for the vertical cell columns of adult neocortex.

Mode of cell migration to the superficial layers of fetal monkey neocortex.

Precise patterns of cell division and migration are crucial to transform the neuroepithelium of the embryonic forebrain into the adult cerebral cortex. Using time-lapse imaging of clonal cells in rat cortex over several generations, we show here that neurons are generated in two proliferative zones by distinct patterns of division. Neurons arise directly from radial glial cells in the ventricular zone (VZ) and indirectly from intermediate progenitor cells in the subventricular zone (SVZ). Furthermore, newborn neurons do not migrate directly to the cortex; instead, most exhibit four distinct phases of migration, including a phase of retrograde movement toward the ventricle before migration to the cortical plate. These findings provide a comprehensive and new view of the dynamics of cortical neurogenesis and migration.

Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases

The blood-brain barrier: an overview: structure, regulation, and clinical implications.

The layers and cells of the early developing central nervous system lack direct counterparts in the adult and must be designated by a special terminology. The inconsistent and inaccurate language now in use leads to misunderstanding and a revision is proposed in which the four fundamental zones are termed the ventricular, subventricular, intermediate, and marginal zones. Each is defined according to the form, behavior, and fate of its constituent cells. All neurons and macroglia of the central nervous system can be derived from these developmental zones.

Embryonic vertebrate central nervous system: Revised terminology

Time of origin of Mauthner's neuron in Xenopus laevis embryos.

The development of the nervous system presents many interesting problems as a developing system with numerous parameters of differentiation as well as from the point of view of the establishment of adult structure and function. With our growing understanding of developmental processes in general, and interactions at various stages of development in particular, it should be profitable to study more closely events of each period in a developing system, looking for information concerning their immediate control and their relation to events of other periods. In the nervous system, one phase which should be investigated much more thoroughly—especially from the point of view of the control of cellular differentiation—is that of the initial appearance of neuroblast cells and formation of the first nerve processes. Most studies of normal embryos which have included the period of initial differentiation have been primarily concerned with tracing the origins of definitive nuclei and fiber tracts, though possible mechanisms controlling various aspects of their development have of course been discussed.

Katherine M. Lyser

Papers

Embryonic vertebrate central nervous system: Revised terminology

Time of origin of Mauthner's neuron in Xenopus laevis embryos.

The development of the chick embryo diencephalon and mesencephalon during the initial phases of neuroblast differentiation.

Differentiation of cells in organ cultures