Early-generated Cells Research Articles

Timing of neurogenesis is a determinant of olfactory circuitry

An odorant receptor map in mammals, that is constructed by the glomerular coalescence of sensory neuron axons in the olfactory bulb, is essential for proper odor information processing. However, how this map is linked with olfactory cortex is unknown. Here, we use a battery of methods, including various markers of cell division in combination with tracers of neuronal connections and time-lapse live imaging, to show that early- and late-generated mouse mitral cells become differentially distributed within the dorsal and ventral subdivisions of the odorant receptor map. In addition, we demonstrate that the late-generated mitral cells extend significantly stronger projections to the olfactory tubercle than the early-generated. Together, these data indicate that the odorant receptor map is developmentally linked to the olfactory cortices in part by the birthdate of mitral cells. This endows different olfactory cortical regions a role to process information from distinct regions of odorant receptor map.

Early-generated preplate neurons in the developing telencephalon: inward migration into the developing striatum.

Specialized subsets of early-generated neurons provide the cellular cues that are necessary for the establishment of characteristic cell and fiber interactions in each brain region. During the development of the mammalian cerebral cortex, the early-generated cells line up in the most superficial part of the telencephalic pallium forming the preplate. It has been generally thought that the preplate derivatives are exclusively located in the cortical region and govern the early histogenetic phase of cortical development. However, we here disclose an unexpected evidence that a subset of early-generated neurons of the piriform preplate migrate inward into and disperse within the subcortical structure striatum during the embryonic stage. Their migratory route is unique and its direction is opposite to the ordinary migration of neuronal precursors directed outward from the periventricular germinal zone. After immigrating into the developing striatum, these early-generated cells are closely associated with the intrastriatal fascicules of axons. The majority of these cells are eliminated by apoptotic cell death during the early postnatal stage. Based on these findings, we propose a new concept: the preplate neurons may not only direct cortical histogenesis but also change their location to play a role in the development of subcortical structures.

Evolution of isocortical organization. A tentative scenario including roles of reelin, p35/cdk5 and the subplate zone.

This paper proposes an evolutionary hypothesis for the origin of (i) the inside-out pattern of mammalian corticogenesis in which late-generated cells become located more superficially than early-generated cells, and (ii) the predominantly radial organization of isocortical inputs in mammals. It is suggested that an outside-in neurogenetic gradient (in which early-generated cells are located more superficially than late-generated cells), as occurs in reptilian cortex, would have positioned the late-produced, associative neurons (destined to supragranular layers in modern isocortex) below the early-produced output neurons. This may have limited the possibilities of synaptic contacts between the younger cells and the afferent terminals which were located in the more superficial layer I. There was probably an adaptive benefit in those individuals in which late-produced cells were capable of passing through the layers of already migrated cells, thus making contacts with superficial afferents and generating corticocortical and local circuits that processed the information before producing an output. Reelin, an extracellular glycoprotein found in layer I, and a cyclin-dependent kinase (cdk5) and its neuronal-specific activator (p35) may have played key roles in the generation of the inside-out gradient. Additionally, by serving as a waiting compartment for thalamic axons while the cortical plate develops, the subplate zone may have participated in the change from an emphasis in a tangential arrangement of thalamic terminals that is characteristic of reptilian cortex to the predominantly radial mode of termination that is observed in mammalian isocortex.

The early neuronal organization predicts the path followed by some major axonal bundles in the embryonic brainstem

In the embryonic CNS, preformed pathways precede the growth of axonal fasciculi [Katz M. J. and Lasek R. J. (1980) Cell Motil. 1, 141–157; Katz M. J. et al. (1980) Neuroscience 5, 821–833]. What are the developmental events that lead to the elaboration of these preformed pathways? To answer this question, we investigated the organization of the primitive neural tube and more particularly the arrangement of the early-generated cells using [ 3H]thymidine autoradiography or bromodeoxyuridine. Our data suggest that the position of early-generated cells might be involved in the setting of such pathways. In the brain stem of E12 0 (12 days and 0 h) and E12 15 rat embryos, the first-generated cells were organized into three longitudinal columns associated with glycoconjugate-rich extracellular spaces in the adjacent primitive marginal layer. Also, axons traced with 1,1′-dioctadecyl-3,3,3′,3′-tetramethyl-indocarbocyanine perchlorate (DiI) were contiguous to the early-generated cellular columns and represented the primordium of the medial longitudinal fasciculus, the lateral longitudinal tract and the mesencephalic trigeminal tract. Our results show a correlation between the organization of early-generated cells, likely neurons, and the pattern of extracellular spaces in the marginal layer where axons grow. It has been reported in the literature that neurons produce elements of the extracellular matrix such as growth-modulating molecules or space-creating molecules. We therefore suggest that the position of early-generated neurons could be involved in the elaboration of a template for the setting of some major longitudinal tracts during embryonic development of the brainstem.

Morphology of pioneer and follower growth cones in the developing cerebral cortex

In the developing nervous systems of both invertebrates and vertebrates, neurons must develop precise sets of axonal connections. One strategy used by both orders of animals is to generate a special class of neurons whose axons "pioneer" the first pathways between these cells and their targets. In the developing mammalian telencephalon, the subplate neurons (which are among the first neurons to be generated in development) extend axons to long-distance subcortical targets before the neurons of the deep cortical layers 5 and 6 have been generated. The axons of layer 5 and 6 neurons later follow a similar pathway to form permanent subcortical projections to the thalamus and tectum, and thereafter the vast majority of subplate neurons die. These results have generated the hypothesis that subplate axons may actually be required for the axons of layer 5 and 6 neurons to innervate their appropriate subcortical targets. The complexity of growth cones has previously been correlated with axonal decision making: differences in growth cone morphologies have been noted in comparisons of leading versus following axons (LoPresti, Macagno, and Levinthal, 1973; Nordlander, 1987; Yaginuma, Homma, Kunzi, and Oppenheim, 1991), and at choice points along axon pathways (Raper, Bastiani, and Goodman, 1983; Tosney and Landmesser, 1985; Caudy and Bentley, 1986a,b; Bovolenta and Mason, 1987; Holt, 1989; Bovolenta and Dodd, 1990; Yaginuma et al., 1991). Thus, as a first step toward addressing the question of whether the axons of deep-layer neurons simply follow subplate axons to their targets, we have studied the morphology of cortical growth cones at various points along the corticothalamic pathway and at different stages of development. We examined the brains of fetal ferrets and cats at ages ranging from embryonic days (E) 24 to E50, using the fluorescent lipophilic tracer 1,1-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (DiI) to reveal the axons and growth cones of cortical neurons. Growth cones were drawn, and quantitative measurements of their complexity were made by counting filopodia and calculating their surface area. No morphological differences were found among growth cones at different points along the corticothalamic pathway at a given age. However, growth cones belonging to early-generated cells (likely to be subplate neurons) are significantly larger and more complex than are the growth cones of later-generated cortical neurons. This evidence is consistent with the suggestion that subplate growth cones actively pioneer the corticothalamic pathway, and that the axons of layer 5 and 6 neurons follow it.