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S M Crain

Publications and source records attributed to S M Crain.

At least 73 records · Page 4Linked to original sources

Projections of growth-cone-bearing fibers of retinal ganglion cells within co-cultured tectal explants: early branching depends on age of target tissue.

The projections of retinal ganglion cell axons within co-cultured tectal explants were analyzed in order to investigate some of the factors that determine the earliest responses of retinal axons to cues present in an isolated target tissue. Half retinas and superior colliculi (tecta) from the embryonal mouse were explanted, separated by a 0.5 mm gap. After 5 days in vitro retinal ganglion cells were labeled by extracellular ionophoresis of HRP into the optic nerve head region. Cleared co-cultures were studied as whole mounts. Growth-cone-bearing retinal fibers were studied in standard tectal co-cultures, and in cases where tectum had been explanted 2 weeks prior to retina. The heterochronously prepared cultures had a higher proportion of fibers with complex branching patterns than the synchronous explants. Cultures in which retinas were explanted 1 week after tecta exhibited intermediate proportions of such fibers. These observations suggest that older tecta facilitate branching of ingrowing retinal fibers, although other alterations during in vitro development must be evaluated. The growth patterns of axons originating in nasal and temporal hemi-retinas were analyzed in terms of possible positional cues provided by the target tecta. Axons originating in temporal hemi-retinas did not show evidence of preferential branching in, or growth toward, appropriate anterior regions of co-cultured tectal explants. In contrast, the majority of nasal retinal axons showed enhanced terminations and complex branching in, and bending towards, the posterior tectum.

Animals↗

Taxol effects on glia in organotypic mouse spinal cord-DRG cultures.

Exposure of organotypic mouse spinal cord-dorsal root ganglion cultures to 1-2 microM taxol for up to 6 days results in a remarkable increase in cytoplasmic microtubules in differentiated oligodendroglia. In contrast, there is a notably smaller change in the microtubule complement of astroglia. This suggests that the regulatory and/or synthetic systems for tubulin in these glial types may differ, and that oligodendroglia appear more responsive to modulation in the levels of tubulin subunits as a result of the action of taxol.

Alkaloids↗

The possible role of "sibling neurite bias" in the coordination of neurite extension, branching, and survival.

In this review we consider a novel mechanism, "sibling neurite bias," which may explain aspects of the coordination of elongation, branching, and resorption among different neurites growing from the same neuronal cell body. In this model, growing neurites which incorporate structural precursors at higher rates would deplete the cellular pool of precursors available to their "sibling" neurites; neurites would compete for survival, but in addition they would bias each other's behavior during active growth. Evidence is reviewed that "sibling neurite bias" may contribute to the establishment and stabilization of specific neural connections. Specific examples examined include the loss of polyinnervation at the developing neuromuscular junction, contextual mapping in the retino-tectal system, and selective neurite growth patterns and synaptic connections in nerve tissue culture model systems.

Animals↗

Development of Met-enkephalin immunoreactivity in organotypic explants of fetal mouse spinal cord and attached dorsal root ganglia.

Radioimmunoassays of methionine-enkephalin (Met-Enk) in organotypic cultures of 13-day fetal mouse spinal cord explants with attached dorsal root ganglia (DRG) demonstrate a progressive development of immunoreactivity (IR) during 5 weeks in vitro. Met-Enk IR in these cultures increased to levels observed in adult rodent spinal cord. most of the Met-Enk IR assays were made on cord explants excised from cord-DRG cultures. In smaller numbers of assays performed on entire DRG-cord cultures or on cord cultured in the absence of DRGs, similar levels of Met-Enk IR were obtained. Thus most of the Met-Enk IR appeared to be located within the cord tissue. No Met-Enk IR was detected in DRGs cultured in the absence of cord. In contrast, low levels of Met-Enk IR were present in about 50% of the assays of DRGs cultured attached to the cord. Since these assays included the neuritic outgrowths of the cultures, our data do not preclude possible contamination by Met-Enk immunoreactive cord neurites that may have aberrantly projected into the outgrowth zones. Nevertheless, the data raise the possibility of a trophic influence of cord tissue on the development of Met-Enk IR in DRG neurons. The development of Met-Enk IR in cord regions of cord-DRG explants extends previous binding assays demonstrating development of opiate receptors in these cultures and provides further support to electrophysiological analyses suggesting tonic opioid inhibitory networks in these explants.

Animals↗

Radiosensitivity and differentiation of ganglion cells within fetal mouse retinal explants in vitro.

Fetal mouse retinas were explanted at 13-14 days of gestation, and exposed to gamma radiation in vitro. Not all regions of the retina were equally susceptible to radiation-induced necrosis; when exposed to 5000 rads soon after explanation, each explant had a single small radioresistant nubbin of apparently intact tissue, located near the optic nerve-head. This region of radioresistant tissue was larger when the dose of radiation was reduced and when the explants were exposed at later times in vitro, indicating the existence of a gradient of radioresistance across retinal explants which spread outward through at least the first week in vitro, the period examined. Based upon the extensive in situ literature which has correlated the emergence of radioresistance with the differentiation of retinal neurons, we conclude that the in situ central-to-peripheral sequence of cellular differentiation continues in vitro within our retinal explants. Whereas the ganglion cell axonal outgrowth from control retinas grown in isolation on collagen substrates underwent a gradual disintegration over 3 weeks in vitro, the sparse axonal outgrowth from explants exposed to 5000 rads disintegrated abruptly at 5-7 days in vitro. This did not appear to be due to direct damage from radiation, but instead reflected the fact that axons in irradiated cultures arose from central retinal regions only, while many axons in control cultures emerged from later-differentiating peripheral regions. We suggest that disintegration of individual axons in the outgrowth may occur rapidly and in a central-to-peripheral sequence. These findings should be useful in designing assays for trophic factors which may prevent ganglion cell axon disintegration in this in vitro model system.

Animals↗

Laminin as a substrate for retinal axons in vitro.

Fetal mouse retinal ganglion cell axons have been shown to ramify within co-cultured basement membrane secreting tumor explants and upon isolated basement membranes. Here we report that laminin, a glycoprotein found in basement membranes and adhesion sites of a variety of cell types, acted as a substrate for retinal explant attachment and axonal outgrowth. When axons were given a direct choice, laminin was preferred over collagen. Under suitable conditions (air-dried upon underlying collagen gels), laminin was more effective than fibronectin for promoting axon emergence from retinal explants. These findings have implications for the study of molecular mechanisms underlying CNS axonal outgrowth.

Animals↗

Hyperexcitability in organotypic mouse hippocampal explants.

We have developed an organotypic hippocampal tissue culture model for analyses of sustained hyperexcitability in which repetitive electric stimulation of the dentate area enhances the amplitude and complexity of evoked normal and epileptiform field potentials recorded extracellularly from CA3/2 areas of neonatal mouse hippocampal explants. In explants where spontaneous field potentials are not detectable at the onset of the experiment, brief repetitive electric stimulation elicits self-sustained epileptiform discharges that continue for the duration of the recorded period (2-10 hours). Lowering the extracellular Ca++ level to 0.1-0.2 mM markedly attenuates these discharges and repetitive stimulation during a 2-4 hr period fails to elicit hyperexcitability. When tested after return to normal media repetitive stimulation can elicit hyperexcitability. Raising the extracellular K+ levels to 8-9 mM enhances the complexity of evoked as well as spontaneous field potentials and, in some cases, elicits self-sustained epileptiform discharges in the absence of repetitive electric stimulation.

Animals↗

Morphological alterations in dorsal root ganglion neurons and supporting cells of organotypic mouse spinal cord-ganglion cultures exposed to taxol.

Explants of 14-day fetal mouse spinal cord with attached dorsal root ganglia, which had become differentiated over 2-3 weeks in culture, were exposed to 1-2 microM taxol for up to 6 days. The culture medium was supplemented with nerve growth factor (300 units/ml) during exposure to the drug. By 3-6 days in taxol, unusually numerous microtubules were seen in peripheral perikaryal and proximal neuritic regions of ganglion neurons. Microtubules also engirdled massive aggregations of pleomorphic vesicular/cisternal elements in many neurons. These aggregates were visible as unusual 'clear' spheroidal regions in the living cells, and were often as large as the nuclei. Some of the elements comprising these striking vesicular/cisternal accumulations appeared to be portions of disrupted Golgi complexes normally polarized around the cytocentrum, as well as hypertrophied smooth endoplasmic reticulum formations. In other neuronal areas, Golgi complexes and other organelles were altered or disrupted to lesser degrees. Ordered microtubular arrays occurred along endoplasmic reticulum cisternae both in neuron somata and neurites. Over time, a plethora of microtubules assembled throughout the perikarya in various orientations apparently unrelated to microtubule organizing centers. Unlike the effects of other plant alkaloids that interact with tubulin, there was no discernible increase in filaments, although their distribution appeared altered. Concentric ordered microtubular-macromolecular lamellated complexes were seen only in neurites. Neuronal nuclei were misshapen, often displaced, and displayed fine structure reminiscent of chromatolysis. Satellite and Schwann cells contained atypically abundant microtubules, abnormal cisternae, disrupted Golgi complexes, and increased lysosomes. Some nuclei displayed abnormal chromatin, and in rare cases even microtubules. We suggest that taxol alters the distribution, integrity, and/or organization of organelle systems in dorsal root ganglion cells by engendering unusually abundant microtubules in abnormal groupings and aberrant locations in these cells.

Alkaloids↗

Phase II trial of mitoguazone in patients with advanced squamous cell carcinoma of the head and neck.

We used mitoguazone (500 mg/m2 iv weekly, with 50-mg/m2 escalations weekly as tolerated) to treat 22 patients with squamous cell carcinoma of the head and neck which recurred after initial therapy. Nine of 22 (11%) patients responded: two had complete responses and seven had partial responses. Gastrointestinal toxicity and anemia were commonly seen. We conclude that mitoguazone is active in squamous cell carcinoma of the head and neck and should be incorporated into phase III trials.

Adult↗

Nerve growth factor attenuates neurotoxic effects of taxol on spinal cord-ganglion explants from fetal mice.

Most neurons in organotypic cultures of dorsal root ganglia from 13-day-old fetal mice require high concentrations of nerve growth factor for survival during the first week after explanation. These nerve growth factor-enhanced sensory neurons mature and innervate the dorsal regions of attached spinal cord tissue even after the removal of exogenous growth factor after 4 days. In cultures exposed for 4 days to nerve growth factor and taxol (a plant alkaloid that promotes the assembly of microtubules) and returned to medium without growth factor, greater than 95 percent of the ganglionic neurons degenerated and the spinal cord tissues were reduced almost to monolayers. In contrast, when the recovery medium was supplemented with nerve growth factor, the ganglionic neurons and dorsal (but not ventral) cord tissue survived remarkably well. Dorsal cord neurons do not normally require an input from dorsal root ganglia for long-term maintenance in vitro, but during and after taxol exposure they become dependent for survival and recovery on the presence of neurite projections from nerve growth-factor-enhanced dorsal root ganglia.

Alkaloids↗

Exposure to 4-aminopyridine prevents depressant effects of opiates on sensory-evoked dorsal-horn network responses in spinal cord cultures.

The depressant effects of morphine (0.1-1 microM) on sensory-evoked dorsal-horn network responses in explants of mouse spinal cord with attached dorsal root ganglia (DRGs) were rapidly restored after addition of 4-aminopyridine (4-AP; 0.1 mM) and major components of these cord responses were stably maintained in the presence of the opiate. Moreover, prior exposure of cord-DRG explants to 0.1 mM 4-AP prevented the depressant effects of 0.1 microM morphine on DRG-evoked dorsal-horn responses, and the effects of 1-10 microM morphine were at least partly antagonized. Increased Ca++ levels (5 microM) attenuated the depression of dorsal horn responses by 1-10 micro M morphine and these effects of Ca++ were greatly enhanced in the presence of 4-AP--in some cultures, concentrations of morphine as high as 100 micro M were strongly antagonized during test periods up to 2 hours. Receptor assays showed that 0.1 mM 4-AP +/- 5 mM Ca++ had no effect on stereospecific opiate binding, indicating that the antagonist actions of these agents in our cultures do not occur at the level of the opiate receptor. The relevance of our in vitro studies of 4-AP antagonism of opiate-depressant effects on sensory-evoked dorsal-horn network responses for analyses of problems in opiate analgesia has been strengthened by a recent report demonstrating that 4-AP does, in fact, reverse morphine analgesia in rats, as determined by tail flick tests.

4-Aminopyridine↗

Development of cross-tolerance to 5-hydroxytryptamine in organotypic cultures of mouse spinal cord-ganglia during chronic exposure to morphine.

Exposure of organotypic explants of mouse spinal cord with attached dorsal root ganglia (DRGs) to low concentrations (approximately 10nM) of 5-hydroxytryptamine (5-HT) markedly depressed sensory-evoked dorsal-horn network responses, resembling the acute effects of opioids in these cultures. Attenuation of cord responses by 5-HT was not prevented by exposure to the 5-HT antagonists, methysergide and cyproheptadiene, nor to the opiate antagonist, naloxone. Explants that had become tolerant to morphine after chronic exposure (1 microM) for greater than 2 days often developed cross-tolerance to 5-HT. Acute exposure of morphine-tolerant explants to naloxone (1 microM) further attenuated the effects of 5-HT so that the minimum depressant levels of 5-HT were often increased up to 30-fold. Increasing the extra-cellular Ca++ concentration (to 5 mM) and/or introduction of 4-aminopyridine markedly antagonized the depressant effects of 5-HT on DRG-evoked cord responses, so that 5-HT levels comparable to those used on morphine-tolerant explants were required to depress naive explants. These depressant effects of 5-HT on cord-DRG explants are consonant with antinociceptive actions of 5-HT administered to dorsal cord in situ. Our data suggest that 5-HT may block neuronal components of dorsal horn networks at similar regions to those that are depressed by opiates, i.g. presynaptic DRG nerve terminals where abundant opiate receptors are located. The marked attenuation of the depressant effects of both 5-HT and opiates on cord-DRG explants by high Ca++ raises the possibility that cross-tolerance to 5-HT in morphine-tolerant explants may result from the same neuronal alterations that render dorsal-horn networks tolerant to opiates. Furthermore, the increased degree of cross-tolerant cultures may be an expression of opiate dependence.

4-Aminopyridine↗

Microtubule arrays in taxol-treated mouse dorsal root ganglion-spinal cord cultures.

Exposure of organotypic dorsal root ganglion-spinal cord cultures to taxol, a potent microtubule promoting and stabilizing agent, results in an unusual abundance of microtubules in neurons, and the presence of microtubule-endoplasmic reticulum arrays in their perikarya and processes. Ordered concentric arrays of microtubules alternating with marcromolecular material are observed in dorsal root ganglion neurites. Short linear structures are discernible between some microtubules and the macromolecular material, as well as between microtubules and endoplasmic reticulum cisternae. Analyses of such unusual microtubule arrays in taxol-treated cultures may provide valuable insights into tubulin-related systems in neurons, as well as in other cells.

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