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R J Franklin

Publications and source records attributed to R J Franklin.

At least 37 records · Page 2Linked to original sources
PubMed2000

The re-expression of the homeodomain transcription factor Gtx during remyelination of experimentally induced demyelinating lesions in young and old rat brain.

Since myelination and remyelination both involve investing an axon with a myelin sheath, a plausible hypothesis is that the two processes involve the expression of similar transcription factors. In this study we have addressed this hypothesis by comparing the expression of messenger RNA of Gtx, a homeodomain transcription factor expressed within oligodendrocytes during myelination, with the expression of messenger RNAs of the major myelin proteins, myelin basic protein and proteolipid protein during remyelination of experimentally induced demyelination in the adult rat brain. We have found a close temporal and spatial association between the expression patterns of the three messenger RNA species during remyelination. By comparing the expression patterns in rapidly remyelinating lesions in young adult rats with slowly remyelinating lesions in old adult rats, we have shown that Gtx messenger RNA expression follows the reappearance of myelin basic protein and proteolipid protein messenger RNAs regardless of the rate of remyelination. This observation demonstrates a clear association between the expression of Gtx messenger RNA and myelin repair. We have also shown that there is a decrease in constitutive levels of expression of myelin basic protein, proteolipid protein and Gtx messenger RNA in old adults compared with young adults. Taken together, our results indicate that Gtx, which has multiple binding sites in the promoter regions of both myelin basic protein and proteolipid protein genes, may have a similar role in the regulation of myelin protein gene expression during remyelination as has been proposed in myelination.

Aging↗
PubMed2000

The Brown Animal Sanatory Institution--historical lessons for the present?

This article briefly reviews the history of the Brown Institution (1871-1944), a remarkable but short-lived and now largely forgotten veterinary centre of research and clinical practice. As well as providing a broad-based clinical service for the surrounding area of London, the Brown Institution was also the home of some of the most distinguished contributors to comparative medicine and physiology. Many of its aspirations, achievements and difficulties are relevant and comparable to those faced by the profession today.

Academies and Institutes↗
PubMed2000

Identification of a human olfactory ensheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons.

The olfactory ensheathing cell (OEC) has attracted much interest recently because of its potential for transplantation-based therapy of CNS disease. Rat OECs are able to remyelinate demyelinated axons and support regeneration of damaged axons. Although OECs can be grown readily from the rat, a macrosmatic species, it has been uncertain whether it would be similarly straightforward to obtain these cells from the human, a microsmatic species with a relatively poorly developed olfactory system. In this study, we have identified a human OEC which shares many properties with its rat counterpart, including expression of the low-affinity nerve growth factor receptor (L-NGFr) and similar growth factor requirements. Purified populations of human OECs obtained by selection with L-NGFr antibodies have extremely high viability in tissue culture, and are capable of remyelinating persistently demyelinated CNS axons following transplantation into experimentally induced demyelinating lesions in the rat spinal cord. Thus, the human OEC represents an important new cell for the development of transplant therapy of CNS diseases.

Animals↗
PubMed1999

Magnetic resonance imaging of transplanted oligodendrocyte precursors in the rat brain.

The lack of any markers for oligodendrocyte precursors that can be visualized within the intact CNS is a significant barrier to trials of transplantation of these cells which aim to enhance remyelination in multiple sclerosis. We have therefore asked whether dextran-coated superparamagnetic iron oxide (SPIO) can be used to label cells prior to transplantation and then visualized within the brain using MRI. We have shown that an oligodendrocyte precursor cell line CG-4 will take up dextran-coated SPIO particles in vitro. The label remains within the cells after transplantation into adult rat brain, as assessed by electron microscopy, and is visible by MRI as a reduction in signal intensity at the transplant site at both 1 and 7 days after surgery. We conclude that MRI detection of SPIO-labelled cells represents a promising and novel approach to the analysis of oligodendroglial cell behaviour following transplantation that has very significant advantages over currently available methods.

Animals↗
PubMed1999

Understanding CNS remyelination: clues from developmental and regeneration biology.

A guiding principle in remyelination research has been to seek clues to its nature in developmental studies on myelination. This "recapitulation hypothesis" argues that the regenerative response involves rerunning much the same programme as occurs during the developmental process. Here we examine the extent to which current evidence supports this hypothesis and whether this is a useful conceptual framework within which to study remyelination and suggest that an equally fruitful approach is to look to regenerative processes in other tissues.

Animals↗
PubMed1999

Demyelination and remyelination of the caudal cerebellar peduncle of adult rats following stereotaxic injections of lysolecithin, ethidium bromide, and complement/anti-galactocerebroside: a comparative study.

Experimentally induced demyelination due to the direct injection of gliotoxic agents has provided powerful models for studying the biology of remyelination. For the most part, these models have involved injection into white matter tracts of the spinal cord. However, the spinal cord has a number of limitations, such as the size of lesions that it is possible to make and its unsuitability for long-term direct cannulation for the delivery of putative remyelination-enhancing agents. In this study, we describe the natural history of three new models of demyelination/remyelination based on the stereotaxic injection of three gliotoxins: lysolecithin, ethidium bromide, and a combination of anti-galactocerebroside antibody and complement (GalC-ab/comp) into the caudal cerebellar peduncle of adult rats. All three agents produced large areas of demyelination with minimal axonal damage, which undergo extensive remyelination. Ethidium bromide- and GalC-ab/comp-induced lesions remyelinated more slowly than those induced by lysolecithin. The contribution to the remyelination of the lesion by Schwann cells reflects the degree of astrocyte damage incurred within the demyelinated area and is greatest for ethidium bromide-induced demyelination. These new models not only provide further insights into the mechanisms of CNS remyelination but also provide a valuable new resource for addressing a series of key issues relevant to current efforts to promote CNS remyelination either by the enhancement of intrinsic processes or by the transplantation of myelinogenic cells.

Animals↗
PubMed1999

Remyelination occurs as extensively but more slowly in old rats compared to young rats following gliotoxin-induced CNS demyelination.

Age is one of the many factors that influence remyelination following CNS demyelination, although it is not clear whether it is the extent or rate of remyelination that is affected. To resolve this issue we have compared remyelination in young and old adult rat CNS following gliotoxin-induced demyelination. Remyelination of areas of ethidium bromide-induced demyelination in the caudal cerebellar peduncle reached completion by 4 weeks in young adult rats (2 months) but was not complete until 9 weeks in old adult rats (9-12 months). We have also shown that remyelination of lysolecithin-induced demyelination in the spinal white matter of old adult rats (18 months) can be extensive, with longer survival times (8 weeks) than have previously been examined. Thus, it is the rate rather than the extent of remyelination that changes in the ageing CNS. These results have important implications for understanding the mechanisms of remyelination, indicating that remyelination need not occur rapidly for it to be extensive. The capacity for the process of remyelination to continue over many weeks must also be borne in mind when assessing remyelination-enhancement strategies either by transplantation or promotion of endogenous mechanisms.

Aging↗
PubMed1999

Distinctive patterns of PDGF-A, FGF-2, IGF-I, and TGF-beta1 gene expression during remyelination of experimentally-induced spinal cord demyelination.

Although remyelination is a well-recognized regenerative process following both experimental and naturally occurring CNS demyelination, remarkably little is known about the molecules involved in its orchestration. In this study we have examined the mRNA expression of seven growth factors that influence oligodendrocyte lineage cells, during the remyelination of lysolecithin-induced demyelination in the rat spinal cord. These lesions involve rapid demyelination of axons, which undergo extensive remyelination between 10 and 28 days. The distribution and levels of expression of PDGF-A, IGF-I, CNTF, FGF-2, TGF-beta1, GGF-2, and NT-3 mRNAs were examined at 2, 5, 7, 10, 14, 21, and 28 days post-lesion induction, both within the lesion and within dorsal root ganglia whose axons transverse the lesion, by quantitative in situ hybridization using 35S-labeled oligonucleotide probes. large increases in IGF-I and TGF-beta1 mRNAs were evident within the spinal cord by 5 days. These levels peaked at 10 days at a time when new myelin sheaths appear and had declined by 28 days. Increases in FGF-2 and PDGF-A mRNAs were less intense and less widely distributed than those of IGF-I and TGF-1, but remained elevated for a longer duration. There were no changes in expression of CNTF, NT-3, or GGF-2 mRNAs within the lesioned cords; neither were ther changes in levels of expression of any growth factor mRNAs in the dorsal root ganglia. This work therefore indicates that some but not all members of the family of growth factors that affect the oligodendrocyte lineage are expressed during remyelination of demyelinated spinal cord axons and provides the data on which future studies on the specific roles of these factors in orchestrating this important regenerative process will be based.

Animals↗
PubMed1999

The expression of myelin protein mRNAs during remyelination of lysolecithin-induced demyelination.

To gain insights into the mechanisms of myelin repair in the CNS and to establish the extent to which this process resembles myelination in development we have examined the patterns of expression of transcripts of the major myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP) during remyelination of lysolecithin-induced demyelination in the adult rat spinal cord. Injection of 1 microliter 1% lysolecithin into the dorsal funiculus caused a dramatic decrease in levels of MBP exon 1 and MBP exon 2-containing transcripts and PLP/DM20 transcripts. Between 10 and 21 days post-lesion induction there was a gradual increase in levels of expression of all transcripts, which had returned to levels associated with normally myelinated spinal cord white matter at 21 days. These increases in levels of expression corresponded to the appearance of remyelinated axons, detected on toluidine blue-stained resin sections. Foci of high levels of expression occurred in regions of the lesion in which new myelin sheath formation was occurring, although the level of expression throughout the lesion never exceeded levels associated with myelin sheath maintenance in normal white matter due to the asynchronous pattern of remyelination. The changes in levels of expression of MBP exon 2 closely followed those of MBP exon 1. Our results indicate that (i) myelin protein gene expression associated with myelinogenesis during remyelination follows a similar pattern to that of myelinogenesis during development and that (ii) in rat models of demyelination changes of expression of MBP exon 1 and exon 2-containing transcripts are of equal value, an observation relevant to quantifying the effects of putative remyelination-enhancing strategies using the lysolecithin model.

Animals↗
PubMed1999

Myelination and behaviour of tenascin-C null transgenic mice.

The extracellular matrix glycoprotein tenascin-C is widely expressed during development and repair, making it surprising that few abnormalities have been found in transgenic mice lacking this molecule. We have therefore re-examined the transgenic mice described by Saga et al. [Saga, Y., Yagi, T., Ikawa, Y., Sakakura, T. & Aizawa, S. (1992) Genes Dev., 6 1821-1831] in which tenascin-C was knocked-out by homologous recombination, focusing on two aspects of the nervous system likely to reveal any abnormalities that might follow the loss of tenascin-C. First, we have determined the pattern of myelin and distribution of oligodendrocyte precursor cells in those areas, such as the optic nerve and retina where local concentrations of tenascin-C have been proposed to act as barriers to oligodendrocyte precursor migration and so prevent inappropriate myelination. Secondly, we have examined the behaviour of the mice in a number of well-characterized tests, e.g. beam-walking, passive avoidance and the Morris water maze. We find no abnormalities of myelination or oligodendrocyte precursor distribution in adult mice, showing that local concentrations of tenascin-C are not the sole mechanism responsible for the pattern of myelination in these regions of CNS. However, we do find a number of behavioural abnormalities in these mice and show that hyperlocomotion and deficits in coordination during beam walking can be ascribed to tenascin-C deficiency. The effects on coordination are, however, not seen on a 129 genetic background. Taken together, these results significantly extend the phenotype associated with tenascin-C deficiency but argue against a role in myelination.

Animals↗
PubMed1998

Paralysis in hedgehogs (Erinaceus europaeus) associated with demyelination.

Paraplegia affected 14 hedgehogs (Erinaceus europaeus) in a wildlife rescue hospital over a period of six months. Postmortem examination revealed demyelination in the brain and spinal cord and an inflammatory response in the meninges, choroid plexus and CNS. The peripheral nervous system was not affected. In the spleen, lungs and liver there was an accumulation of megakaryocytes and other evidence of extramedullary haemopoiesis, but there was no haematological evidence of anaemia. The pattern of disease incidence and the nature of the changes in the CNS suggest they were of viral origin, but no causal agent was isolated and the possibility of a neurotoxin cause cannot be ruled out.

Animals↗
PubMed1998

Transplanting myelin-forming cells into the central nervous system: principles and practice.

Although transplantation of myelin-forming cells into the central nervous system (CNS) has recently attracted much attention as a potential therapy for repairing persistent demyelination found in the demyelinating diseases such as multiple sclerosis and the leukodystrophies, it is worth remembering that the technique was originally conceived of as an experimental technique for manipulating in vivo environments to study interactions between different cell types in either repair or development. It is in this capacity that the technique is still predominantly used. Nevertheless, information, both technical and biological, that the continued use of the technique yields also often provides material for assessing the feasibility of glial cell transplantation as a therapeutic procedure. In this article, we describe some of the guiding principles of transplantation of myelinogenic cells into the mammalian CNS, focusing initially on the recipient environment and then considering the donor material. The division of the discussion into recipient and donor is one of convenience since in reality the interactions between the two cannot be considered in isolation.

Animals↗
PubMed1998

The expression of myelin basic protein exon 1 and exon 2 containing transcripts during myelination of the neonatal rat spinal cord--an in situ hybridization study.

During myelination, myelin proteins are expressed in a highly coordinated sequence. Of the four major isoforms of myelin basic protein, the proportion of the 21.5kDa and 17 kDa isoforms (which contain sequences encoded by myelin basic protein [MBP] exon 2) is enriched during active myelination in the mouse, suggesting that the alternative splicing of MBP transcripts containing exon 2 information is developmentally regulated. In this study, we compare the expression of MBP exon 1 and MBP exon 2 mRNAs in the neonatal rat spinal cord to establish whether developmental regulation of exon 2 mRNAs occurs in the rat in a manner similar to that previously described in the mouse. The expression of MBP mRNAs, together with that of proteolipid protein (PLP/DM-20) mRNA, in the developing white matter tracts increased dramatically between P7 and P10, corresponding to an increase in the extent of myelination. High levels of expression of each mRNA species examined were maintained between P10 and P14 as myelination proceeded. At P21, the expression of MBP exons 1 and 2 was reduced in the ventrolateral funiculi but was maintained at high levels in the dorsal funiculus. At P45, a further downregulation of both MBP mRNAs was apparent. By contrast, high levels of PLP/DM-20 expression were maintained from P10 onwards. In the grey matter, expression of MBP and PLP/DM-20 mRNAs increased more gradually and peak expression occurred later than in the white matter tracts. In this study, we therefore provide a description of myelin protein gene expression during post-natal development of the rat spinal cord. We have also shown that in the rat spinal cord, changes in the levels of MBP exon 2 expression associated with myelination reflect the changes of all MBP transcripts.

Alternative Splicing↗
PubMed1998

Trapidil-mediated inhibition of CNS remyelination results from reduced numbers and impaired differentiation of oligodendrocytes.

In a previous study, we described the inhibitory effects of the growth factor-antagonist, trapidil, on spontaneously occurring oligodendrocyte remyelination in the rat spinal cord following lysolecithin-induced demyelination [30]. The objective of the present study was to further investigate the mechanisms of trapidil-mediated impairment of remyelination and thus obtain greater insight into the steps at which growth factors may be involved in remyelination. To this end, an ultrastructural analysis of the cellular composition of lesions from control and trapidil-treated animals was undertaken. Demyelination was created in the dorsal funiculus of 6-week-old female rats by the injection of 1.0 microliter of 1% lysolecithin. The animals received daily intraperitoneal injections of trapidil (80 mg/kg) or saline for 21 days, beginning on the day of lesion induction. Quantitative electron microscopic examination of lesions from both groups of animals showed that trapidil-treated lesions had reduced numbers of oligodendrocytes (P = 0.02) with a higher relative proportion of immature phenotypes, but increased numbers of microglia (P = 0.0009) and dystrophic axons (P0.02). In addition, the numbers of myelin lamellae around remyelinated axons were fewer in trapidil-treated animals. These results suggest that trapidil-mediated impairment of CNS remyelination is due to a blockage of growth factor-mediated proliferation and/or recruitment of remyelinating cells. Furthermore, the presence of oligodendrocytes with a more immature phenotype and the decreased thickness of the myelin sheaths of remyelination in the trapidil-treated animals indicate an impairment of growth factor-mediated differentiation.

Animals↗