PubMed Health⌕ Search

Biomedical subjects

S K McConnell

Publications and source records attributed to S K McConnell.

At least 19 recordsLinked to original sources
PubMed1995

Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis.

Neurons in the mammalian central nervous system are generated from progenitor cells near the lumen of the neural tube. Time-lapse microscopy of dividing cells in slices of developing cerebral cortex reveals that cleavage orientation predicts the fates of daughter cells. Vertical cleavages produce behaviorally and morphologically identical daughters that resemble precursor cells; these symmetric divisions may serve to expand or maintain the progenitor pool. In contrast, horizontally dividing cells produce basal daughters that behave like young migratory neurons and apical daughters that remain within the proliferative zone. Notch1 immunoreactivity is distributed asymmetrically in mitotic cells, with Notch1 inherited selectively by the basal (neuronal) daughter of horizontal divisions. These results provide cellular and molecular evidence that cortical neurons are generated from asymmetric divisions.

Animals↗
PubMed1995

Tangential migration of neurons in the developing cerebral cortex.

The mammalian cerebral cortex is divided into functionally distinct areas. Although radial patterns of neuronal migration have been thought to be essential for patterning these areas, direct observation of migrating cells in cortical brain slices has revealed that cells follow both radial and nonradial pathways as they travel from their sites of origin in the ventricular zone out to their destinations in the cortical plate (O'Rourke, N.A., Dailey, M.E., Smith, S.J. and McConnell, S.K. (1992) Science 258, 299-302). These findings suggested that neurons may not be confined to radial migratory pathways in vivo. Here, we have examined the patterns of neuronal migration in the intact cortex. Analysis of the orientations of [3H]thymidine-labeled migrating cells suggests that nonradial migration is equally common in brain slices and the intact cortex and that it increases during neurogenesis. Additionally, cells appear to follow nonradial trajectories at all levels of the developing cerebral wall, suggesting that tangential migration may be more prevalent than previously suspected from the imaging studies. Immunostaining with neuron-specific antibodies revealed that many tangentially migrating cells are young neurons. These results suggest that tangential migration in the intact cortex plays a pivotal role in the tangential dispersion of clonally related cells revealed by retroviral lineage studies (Walsh, C. and Cepko, C. L. (1992) Science 255, 434-440). Finally, we examined possible substrata for nonradial migration in dorsal cortical regions where the majority of glia extend radially. Using confocal and electron microscopy, we found that nonradially oriented cells run perpendicular to glial processes and make glancing contacts with them along their leading processes. Thus, if nonradial cells utilize glia as a migratory substratum they must glide across one glial fiber to another. Examination of the relationships between migratory cells and axons revealed axonal contacts with both radial and nonradial cells. These results suggest that nonradial cells use strategies and substrata for migration that differ from those employed by radial cells.

Animals↗
PubMed1995

Strategies for the generation of neuronal diversity in the developing central nervous system.

During development, the neural tube produces a large diversity of neuronal phenotypes from a morphologically homogeneous pool of precursor cells. In recent years, the cellular and molecular mechanisms by which specific types of neurons are generated have been explored, in the hope of discovering features common to development throughout the nervous system. This article focuses on three strategies employed by the CNS to generate distinct classes of neuronal phenotypes during development: dorsal-ventral polarization in the spinal cord, segmentation in the hindbrain, and a lamination in the cerebral cortex. The mechanisms for neurogenesis exemplified by these three strategies range from a relatively rigid, cell lineage-dependent specification with a high degree of subservance to early patterns of gene expression, to inductions and cell-cell interactions that determine cell fates more flexibly.

Animals↗
PubMed1994

Subplate pioneers and the formation of descending connections from cerebral cortex.

The adult cerebral cortex extends axons to a variety of subcortical targets, including the thalamus and superior colliculus. These descending projections are pioneered during development by the axons of a transient population of subplate neurons (McConnell et al., 1989). We show here that the descending axons of cortical plate neurons appear to be delayed significantly in their outgrowth, compared with those of subplate neurons. To assess the possible role of subplate neurons in the formation of these pathways, subplate neurons were ablated during the embryonic period. In all cases, an axon pathway formed from visual cortex through the internal capsule and into the thalamus. In half of all cases, however, cortical axons failed to invade their normal subcortical targets. In the other half, targets were innervated normally. Subplate neurons are therefore likely to provide important cues that aid the process by which cortical axons grow toward, select, and invade their subcortical targets.

Afferent Pathways↗
PubMed1994

Regulation of the POU domain gene SCIP during cerebral cortical development.

The mammalian cerebral cortex is patterned into layers of neurons that share characteristic morphologies, physiological properties, and axonal connections. Neurons in the various layers are thought to acquire their lamina-specific identities shortly before the time of their final mitosis in the cortical ventricular zone. In order to investigate the molecular basis of laminar patterning in the CNS, we have performed in situ hybridization studies of the POU homeodomain gene SCIP (also known as Tst-1 or Oct-6), which is expressed in proliferating Schwann cells in the PNS and O2A progenitor cells in the developing CNS. In the CNS of adult rats, SCIP is expressed at high levels in the cerebral cortex, specifically in layer 5 pyramidal neurons that form subcortical axonal connections. SCIP is both temporally and spatially regulated during cortical development. Its initial expression in the intermediate zone and cortical plate is correlated with the early migration and differentiation of layer 5 neurons. SCIP hybridization was not, however, observed within the ventricular zone during the period of neurogenesis. SCIP is also expressed at high levels in the neurons of cortical layer 2/3, during their migration and differentiation within the cortical plate. This expression in the upper layers is apparently downregulated during postnatal periods, with the adult pattern apparent by postnatal day 30 (P30). POU domain genes are thought to play a role in cell lineage and cell fate decisions in several systems; thus, SCIP may serve a function in generating discrete laminar phenotypes in the developing cerebral cortex. In addition, since SCIP is a putative repressor of myelin gene expression, our results suggest that SCIP plays a role in regulating transcription in differentiated CNS neurons as well as in proliferating glial precursors.

Aging↗
PubMed1994

Otx1 and Otx2 define layers and regions in developing cerebral cortex and cerebellum.

Within the cerebral and cerebellar cortices, neurons are organized in layers that segregate neurons with distinctive morphologies and axonal connections, and areas or regions that correspond to distinct functional domains. To explore the molecular underpinnings of pattern formation in layered regions of the CNS, we have characterized the patterns of expression of two homeodomain genes, Otx1 and Otx2, by in situ hybridization during embryonic and postnatal development in the rat. Otx1 and Otx2 are vertebrate homologs of the Drosophila gap gene orthodenticle, and are expressed during the development of the murine CNS (Simeone et al., 1992). Here we report that Otx1 mRNA is expressed in a subpopulation of neurons within cortical layers 5 and 6 during postnatal and adult life. This gene is also expressed by the precursors of deep-layer neurons within the developing cerebral ventricular zone, but is apparently downregulated by the progenitors of upper-layer neurons; Otx1 is never expressed by the neurons of layers 1-4. The spatial and temporal patterns suggest that Otx1 may play a role in the specification or differentiation of neurons in the deep layers of the cerebral cortex. Within the cerebellum, mRNAs for Otx1 and Otx2 are found within the external granular layer (EGL), but in three spatially distinct domains. During postnatal development, Otx1 is expressed within anterior cerebellar lobules; Otx2 mRNA is localized posteriorly, and a region of overlap in mid-cerebellum defines a third domain in which both genes are expressed. The boundaries of Otx1 and Otx2 expression correspond to the major functional boundaries of the cerebellum, and define the vestibulocerebellum, spinocerebellum, and pontocerebellum, respectively. Spatially restricted patterns of hybridization are observed early in postnatal life, at times that correspond roughly to the invasion of spinal and pontine afferents into the cerebellum (Arsénio-Nunes and Sotelo, 1985; Mason, 1987). These results raise the possibility that Otx1 and Otx2 play a role in cerebellar regionalization during early development.

Amino Acid Sequence↗
PubMed1994

Differential expression of synaptic vesicle protein 2 (SV2) isoforms.

The synaptic vesicle proteins SV2A and SV2B (SV2 = synaptic vesicle protein 2) are two highly related proteins belonging to a family of transporters. As a first step toward identifying the function of the SV2 proteins, we examined the expression of SV2A and SV2B in the rat brain by in situ hybridization, immunohistochemistry, and immunoprecipitation with isoform-specific antibodies. These analyses revealed that one isoform, SV2A, is expressed ubiquitously throughout the brain at varying levels. The other isoform, SV2B, has a more limited distribution with varying degrees of coexpression with SV2A. Immunoprecipitation of brain synaptic vesicles with isoform-specific antibodies followed by Western analyses suggests that both isoforms can be present on the same synaptic vesicle. The expression of the SV2 proteins did not correlate either with neurotransmitter phenotype or with the expression of other synaptic vesicle protein isoforms. SV2B expression was observed to change during development; it is more widely expressed in the immature brain and is found in cells that have yet to establish synaptic contacts. The ubiquitous and overlapping expression of the SV2s suggests that they perform a function common to all synaptic vesicles. Variable and changing coexpression of the SV2 isoforms may indicate that SV2 function is regulated by the isoform composition of synaptic vesicles. The observation that the synaptic vesicle proteins, all occurring in multiple isoforms, are differentially expressed with respect to each other indicates that up to 90 different vesicle types are possible.

Animals↗
PubMed1992

Diverse migratory pathways in the developing cerebral cortex.

During early development of the mammalian cerebral cortex, young neurons migrate outward from the site of their final mitosis in the ventricular zone into the cortical plate, where they form the adult cortex. Time-lapse confocal microscopy was used to observe directly the dynamic behaviors of migrating cells in living slices of developing cortex. The majority of cells migrated along a radial pathway, consistent with the view that cortical neurons migrate along radial glial fibers. A fraction of cells, however, turned within the intermediate zone and migrated orthogonal to the radial fibers. This orthogonal migration may contribute to the tangential dispersion of clonally related cortical neurons.

Animals↗
PubMed1992

The control of neuronal identity in the developing cerebral cortex.

Recent studies of the lineages and developmental potential of cortical neurons show that cell fates are progressively restricted during cerebral cortical development. Cell lineage experiments suggest that individual cortical precursors are multipotent, as their progeny can end up in different cortical areas, and in different layers within an area. Transplantation studies have shown that young neurons are committed very early on to adopting a given laminar position, in a manner correlated with their birth date in the ventricular zone. Neurons in different neocortical areas, however, retain a functional and anatomical equipotentiality well into cortical development, suggesting that positional cues determine a cell's area-specific identity.

Animals↗
PubMed1991

Cell cycle dependence of laminar determination in developing neocortex.

The neocortex is patterned in layers of neurons that are generated in an orderly sequence during development. This correlation between cell birthday and laminar fate prompted an examination of how neuronal phenotypes are determined in the developing cortex. At various times after labeling with [3H]thymidine, embryonic progenitor cells were transplanted into older host brains. The laminar fate of transplanted neurons correlates with the position of their progenitors in the cell cycle at the time of transplantation. Daughters of cells transplanted in S-phase migrate to layer 2/3, as do host neurons. Progenitors transplanted later in the cell cycle, however, produce daughters that are committed to their normal, deep-layer fates. Thus, environmental factors are important determinants of laminar fate, but embryonic progenitors undergo cyclical changes in their ability to respond to such cues.

Animals↗
PubMed1991

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.

Animals↗
PubMed1990

The specification of neuronal identity in the mammalian cerebral cortex.

The determination of neuronal fate in the developing cerebral cortex has been studied by tracking normal cell lineages in the cortex, and by testing the commitment of young cortical neurons to their normal fates. These studies together suggest that neuronal progenitors are multipotent during development and have the potential to produce neurons destined for many or all of the cortical layers. However, the laminar identity of an individual neuron appears to be specified through environmental interactions at the time of the cell's terminal mitotic division, prior to its migration into the cortical plate.

Animals↗
PubMed1990

Requirement for subplate neurons in the formation of thalamocortical connections.

The neurons of layer 4 in the adult cerebral cortex receive their major ascending inputs from the thalamus. In development, however, thalamic axons arrive at the appropriate cortical area long before their target layer 4 neurons have migrated into the cortical plate. The axons accumulate and wait in the zone below the cortical plate, the subplate, for several weeks before invading the cortical plate. The subplate is a transient zone that contains the first postmitotic neurons of the telencephalon. These neurons mature well before other cortical neurons, and disappear by cell death after the thalamic axons have grown into the overlying cortical plate. The close proximity of growing thalamocortical axons and subplate neurons suggests that they might be involved in interactions important for normal thalamocortical development. Here we show that early in development the deletion of subplate neurons located beneath visual cortex prevents axons from the lateral geniculate nucleus of the thalamus from recognizing and innervating visual cortex, their normal target. In the absence of subplate neurons, lateral geniculate nucleus axons continue to grow in the white matter past visual cortex despite the presence of their target layer 4 neurons. Thus the transient subplate neurons are necessary for appropriate cortical target selection by thalamocortical axons.

Animals↗