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R L Sidman

Publications and source records attributed to R L Sidman.

At least 37 records · Page 2Linked to original sources
PubMed1993

PCR analysis of DNA from 70-year-old sections of rodless retina demonstrates identity with the mouse rd defect.

Rodless retina (gene symbol, r) was discovered in mice by Keeler 70 years ago and was first described in this journal as an autosomal recessive mutation leading to "the absence of the visual cells (rods), the external nuclear layer, and the external molecular layer" [Keeler, C. E. (1924) Proc. Natl. Acad. Sci. USA 10, 329-333]. The mutation was studied by Keeler and others in the United States and Europe over the next decade, but Keeler's stock was destroyed in 1939, and mice definitively related to his by pedigree and progeny tests also appeared to have been lost by the end of World War II. In the early 1950s Brückner in Basel recognized mice with a similar retinal phenotype. Investigators in London and Strasbourg analyzed descendants of Brückner's mice and concluded, on the basis of different pathogenesis from r, that they carried a new mutation, which came later to be called retinal degeneration, rd. The relationship of r and rd has been unsettled ever since. Now that the rd phenotype is known to be due to a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene, we hoped to settle the question by direct analysis of r DNA. DNA was liberated from 70-year-old histological sections of +/r and r/r eyes, the only extant r DNA, and the regions encompassing the nonsense mutation amplified by the polymerase chain reaction (PCR). Sequence analysis of the PCR products revealed the presence of the same nonsense mutation and two intron polymorphisms in r DNA. PCR and direct sequence analysis of 11 strains of mice known to carry rd (or a similar allele) also revealed the presence of the nonsense mutation and the same intron polymorphisms. The fact that all r and rd mice contain an identical defect and intron polymorphisms in the phosphodiesterase beta-subunit gene settles beyond reasonable doubt that a single mutation arising > 70 years ago is now widely distributed through inbred mouse strains. Because of the extensive use of the name in publications of the past 40 years, we propose that the gene continue to be designated retinal degeneration, rd.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1993

Differentiation and axonal outgrowth pattern of fetal dorsal root ganglion cells orthotopically allografted into adult rats.

Fetal allogeneic dorsal root ganglia (DRG) between 13 and 15 days (E13-E15) were transplanted into the enucleated fourth and fifth lumbar (L4, L5) ganglionic capsules of adult rat hosts. Some of the grafts were prelabeled with the vital carbocyanine dye DiI. Three to 9 months later, neuroanatomic tracers were applied singly or in combination to the sciatic nerve at a transection site 2-3 cm distal to the ganglion and to the dorsal quadrant of the spinal cord. Tissues in selected cases were stained with antibodies to calcitonin gene-related peptide (CGRP) or to neurofilament protein (antibody RT-97) as evidence of neuronal differentiation and axonal growth. In two grafted animals serial sections were made across the root-cord junction which was examined by light and electron microscopy. This material was compared to similarly prepared sections from two nongrafted animals subjected to dorsal root crush. Some grafted ganglion neurons survived for the 3-9 months of the study. Many of these cells became labeled after tracers were applied to the peripheral nerve, to the lumbar spinal cord, or to both. Additional signs of differentiation included expression of CGRP and neurofilament protein immunoreactivity in neuronal cell bodies and processes. Electron microscopic examination showed many small diameter fibers, both myelinated and unmyelinated, in the grafted root on both sides of the PNS/CNS junction. The results with this orthotopic transplantation model show that fetal DRG neurons can differentiate in an adult host and grow axonal branches into peripheral nerves as well as centrally through the dorsal root toward the spinal cord. In addition, our findings suggest that some of the centrally growing fibers cross the PNS/CNS border into the mature spinal cord.

Animals↗
PubMed1992

A leucine-to-proline mutation in the putative first transmembrane domain of the 22-kDa peripheral myelin protein in the trembler-J mouse.

Peripheral myelin protein PMP-22 is a potential growth-regulating myelin protein that is expressed by Schwann cells and predominantly localized in compact peripheral myelin. A point mutation in the Pmp-22 gene of inbred trembler (Tr) mice was identified and proposed to be responsible for the Tr phenotype, which is characterized by paralysis of the limbs as well as tremors and transient seizures. In support of this hypothesis, we now report the fine mapping of the Pmp-22 gene to the immediate vicinity of the Tr locus on mouse chromosome 11. Furthermore, we have found a second point mutation in the Pmp-22 gene of trembler-J (TrJ) mice, which results in the substitution of a leucine residue by a proline residue in the putative first transmembrane region of the PMP-22 polypeptide. Tr and TrJ were previously mapped genetically as possible allelic mutations giving rise to similar, but not identical, phenotypes. This finding is consistent with the discovery of two different mutations in physicochemically similar domains of the PMP-22 protein. Our results strengthen the hypothesis that mutations in the Pmp-22 gene can lead to heterogeneous forms of peripheral neuropathies and offer clues toward possible explanations for the dominant inheritance of these disorders.

3T3 Cells↗
PubMed1992

Trembler mouse carries a point mutation in a myelin gene.

The autosomal dominant trembler mutation (Tr), maps to mouse chromosome 11 (ref. 2) and manifests as a Schwann-cell defect characterized by severe hypomyelination and continuing Schwann-cell proliferation throughout life. Affected animals move clumsily and develop tremor and transient seizures at a young age. We have recently described a potentially growth-regulating myelin protein, peripheral myelin protein-22 (PMP-22; refs 7, 8), which is expressed by Schwann cells and found in peripheral myelin. We now report the assignment of the gene for PMP-22 to mouse chromosome 11. Cloning and sequencing of PMP-22 complementary DNAs from inbred Tr mice reveals a point mutation that substitutes an aspartic acid residue for a glycine in a putative membrane-associated domain of the PMP-22 protein. Our results identify the PMP-22 gene as a likely candidate for the mouse trembler locus and will encourage the search for mutations in the corresponding human gene in pedigrees with hypertrophic neuropathies such as Charcot-Marie-Tooth and Dejerine-Sottas diseases (hereditary motor and sensory neuropathies I and III).

Amino Acid Sequence↗
PubMed1992

Centrifugal growth in orthotopic grafts of allogeneic dorsal root ganglia in adult rats: evidence for possible central ingrowth?

Fetal allogeneic dorsal root ganglion (DRG) transplants from 13-15 day rat embryo's (E13-E15) survived and differentiated when grafted orthopically (within the capsules of the excised 4th and 5th lumbar (L4-L5) ganglia) in adult rats. Survival of grafted neurones was established by prelabeling the grafts with a fluorescent vital dye (DiI) and visualizing the retained fluorescent marker 3 to 9 months later. Simultaneous retrograde tracing using fluorescent tracers applied in the spinal cord and peripheral nerve, respectively, yielded double-labeled dorsal root ganglion neurons, some of which were prelabeled. These findings demonstrate that prelabeled E13-E15 ganglia survive orthopic grafting, organotypically differentiate into mature DRG neurones, and can be double-labeled with fluorescent dyes applied to their peripherally and centrally directed processes. The presence of DiI containing cells which were retrogradely labeled from the spinal cord suggests that fetal (E13-E15) ganglia may have the capability of growing into a mature spinal cord.

Aging↗
PubMed1992

Morphometric analysis of normal, mutant, and transgenic CNS: correlation of myelin basic protein expression to myelinogenesis.

The neurological mutant mice shiverer (shi) and myelin deficient (shimld) lack a functional gene for the myelin basic proteins (MBP), have virtually no myelin in their CNS, shiver, seize, and die early. Mutant mice homozygous for an MBP transgene have MBP mRNA and MBP in net amounts approximately 25% of normal, have compact myelin, do not shiver or seize, and live normal life spans. We bred mice with various combinations of the normal, transgenic, shi, and shimld genes to produce mice that expressed MBP mRNA at levels of 0, 5, 12.5, 17.5, 50, 62.5, and 100% of normal. The CNS of these mice were analyzed for MBP content, tissue localization of MBP, degree of myelination, axon size, and myelin thickness. MBP protein content correlated with predicted MBP gene expression. Immunocytochemical staining localized MBP to white matter in normal and transgenic shi mice with an intensity of staining comparable to the degree of MBP gene expression. An increase in the percentage of myelinated axons and the thickness of myelin correlated with increased gene expression up to 50% of normal. The percentage of myelinated axons and myelin thickness remained constant at expression levels greater than 50%. The presence of axons loosely wrapped with oligodendrocytic membrane in mice expressing lower amounts of MBP mRNA and protein suggested that the oligodendroglia produced sufficient MBP to elicit axon wrapping but not enough to form compact myelin. Mean axon circumference of myelinated axons was greater than axon circumference of unmyelinated axons at each level of gene expression, further evidence that oligodendroglial cells preferentially myelinate axons of larger caliber.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Databases for neuroscience.

Databases for neuroscience must handle large volumes of image and graphical data as well as domain knowledge. Several software development efforts are addressing these issues in an attempt to aid the acquisition, analysis and exchange of complex data sets.

Databases, Bibliographic↗
PubMed1991

Direct spread of reovirus from the intestinal lumen to the central nervous system through vagal autonomic nerve fibers.

A crucial event in the pathogenesis of systemic enteric virus infections is entry of virus into the nervous system. Whether enteric virus spreads from the intestinal tract to the central nervous system through nerves or through the bloodstream was examined using a serotype 3 reovirus strain. After peroral inoculation of newborn mice with reovirus, serial histologic sections of small intestine, brain and spinal cord were prepared and stained by immunoperoxidase to detect viral antigen. Three days after inoculation, viral antigen was observed in mononuclear cells of ileal Peyer's patches and in neurons of the adjacent myenteric plexus. Infection first appeared in the central nervous system 1-2 days later in neurons of the dorsal motor nucleus of the vagus nerve. Endothelial cells, meninges, choroid plexus, hypothalamus, and area postrema were not infected, indicating neural rather than bloodborne spread from the intestine. Staining of neurons in the dorsal motor nucleus of the vagus nerve depended on the route of virus inoculation and was independent of the amount of virus in the bloodstream. These results demonstrate that an enteric virus entering a host from the intestinal lumen can spread to the central nervous system through nerve fiber innervating the intestine.

Animals↗
PubMed1990

Identification and mapping of a mouse gene influencing cerebellar folial pattern.

Little is known about the role of inheritance in the pattern of cerebral and cerebellar cortical folding, or the causes of individual variation. Inouye and Oda (J. Comp. Neurol., 190 (1980) 357-362) found that the cerebellar folial pattern varies markedly between inbred strains of mice and between individuals in a closed (non-inbred) colony, but shows little variation between individuals within a given inbred strain. They concluded that strain-specific variation in cerebellar folial pattern is under genetic control. In the present study, the folial pattern was examined in crosses between the C57BL/6J and DBA/2J inbred strains of mice, which differ in the presence or absence of a single cerebellar fissure, and in recombinant inbred strains derived from a cross between the same strains. We found that variation is discrete, that neither phenotype is dominant, and that the strain difference is due predominantly to allelic differences at a single locus (Cfp-1) on chromosome 4. Incomplete penetrance of the simpler pattern suggests that this genetic locus interacts in a probabilistic manner with epigenetic mechanisms involved in morphogenesis of the cerebellum.

Animals↗
PubMed1989

Persistent hypersynchronization of neocortical neurons in the mocha mutant of mouse.

A recessive mutation in the mouse at the mocha locus (mh, chromosome 10) modulates the synchronous synaptic activation of neocortical neurons, resulting in a constant 6-7 Hz (theta) wave pattern in the electrocorticogram. The gene-linked brain rhythm is unaffected by motor behavior and cannot be desynchronized by sensory stimuli. This exemplary neurological mutation affecting cortical excitability is the first to reveal clearly that the predominance of a specific pattern of spontaneous brain wave activity can be inherited as a recessive trait.

Animals↗
PubMed1988

Long lives for homozygous trembler mutant mice despite virtual absence of peripheral nerve myelin.

Nervous system functions are dependent on point-to-point communication of signals along neuronal axons, and axonal insulation by myelin is thought to speed such conduction. Loss of previously formed myelin or lack of myelin formation can have serious, even fatal, consequences. Mice homozygous for the trembler mutation make virtually no peripheral nervous system myelin, yet have long and functional lives. This result calls into question the view that peripheral nervous system myelin plays a vital role, at least in this species.

Animals↗
PubMed1988

Positional variations in germinal cell growth in pigment-chimeric eyes of Xenopus: posterior half of the developing eye studied in genetic chimerae and in computer simulations.

Growth of germinal cells at different angular positions within the posterior portion of the embryonic frog eye has been examined by orthotopically transplanting small groups of germinal cells from pigmented (stage 30-38) donor embryos into albino (stage 28-36) hosts and then serially photographing the polyclonal-cell progeny domain (typically a black sector) in the pigmented retinal epithelium of the living, growing eye. Far-ventral (6 o'clock) germinal cells formed a narrow sector along the ventral fissure, but ventral germinal cells at a position just posterior to the fissure (7 o'clock on a right eye) were seen to expand rapidly their angular territory on the germinal zone and formed huge sectors that widened toward the front of the older larval eye. Posterior (8, 9, and 10 o'clock) germinal cells were seen to shift their angular positions gradually toward dorsal and formed sectors that appeared to veer dorsalward nearing the front of the older eye. Dorsal (11 o'clock) germinal cells showed attenuative growth, forming sectors that narrowed approaching the front of the older eye. A simulation model of the growth dynamic was used to examine how expansive growth ventrally drives the positional variations in growth. When far-ventral germinal cells were programmed to retain the 6 o'clock position and ventral (7 o'clock) germinal cells were programmed to divide symmetrically at a high probability to produce two daughter germinal cells, not only were the observed ventral chimeric patterns simulated, but also simulated were the attenuative growth of dorsal transplants and the dorsal displacement and veering seen in the growth of posterior transplants.

Animals↗
PubMed1987

Expression of a myelin basic protein gene in transgenic shiverer mice: correction of the dysmyelinating phenotype.

Mice homozygous for the autosomal recessive mutation shiverer (shi) lack myelin basic protein (MBP) and exhibit a distinct behavioral pattern including tremors (shivering), convulsions, and early death. We have previously demonstrated that shiverer mice have a partial deletion in the gene encoding MBP. We now have introduced the wild-type MBP gene into the germ line of shiverer mice by microinjection into fertilized eggs. Transgenic shiverer mice homozygous for the introduced gene have MBP mRNA and protein levels that are approximately 25% of normal, and produce compacted myelin with major dense lines. Correct temporal and spatial expression of the MBP gene is achieved with a genomic MBP cosmid clone containing 4 kb of 5' flanking sequence and 1 kb of 3' flanking sequence. Moreover, the four different forms of MBP produced by alternative patterns of RNA splicing are present. These homozygous transgenic shiverer mice no longer shiver nor die prematurely.

Alleles↗
PubMed1987

Myelin deficient mice: expression of myelin basic protein and generation of mice with varying levels of myelin.

Mice homozygous for the mutation myelin deficient (mld), an allele of shiverer, exhibit decreased CNS myelination, tremors, and convulsions of progressively increasing severity leading to an early death. In this report we demonstrate in mld mice that the gene encoding myelin basic protein (MBP) is expressed at decreased levels and on an abnormal temporal schedule relative to the wild-type gene. Southern blot analyses, field-inversion gel electrophoresis studies, and analyses of mld MBP cosmid clones indicate that there are multiple linked copies of the MBP gene in mld mice. We have introduced an MBP transgene into mld mice and found that myelination increases and tremors and convulsions decrease. Mld and shiverer mice with zero, one, or two copies of the MBP transgene express distinct levels of MBP mRNA and myelin. The availability of a range of mice expressing graded levels of myelin should facilitate quantitative analysis of the roles of MBP in the myelination process and of myelin in nerve function.

Alleles↗
PubMed1987

Growth and development of the mouse retinal pigment epithelium. I. Cell and tissue morphometrics and topography of mitotic activity.

A computer-assisted morphometric and kinetic analysis of retinal pigment epithelium (PE) development was carried out in C57BL/6J and hybrid mice from Embryonic Day 13 (E13) to Postnatal Day 250 (P250). Total cell number rose from 14,000 at E15 at the rate of about 4000 cells/day to P1 and then at about 1500 cells/day to reach a stable level of 54,000 cells at P15. Compared to the 4-fold rise in cell number, PE area increased about 10-fold, in part through cell hypertrophy which continued beyond P15. Cell concentration increased with distance from the optic nerve head during development, but the gradient disappeared by P20 except for a consistent population of small cells around the optic nerve head and a late-appearing population of very large cells at the ora serrata. Binucleate cells constitute 2.1% of the PE cell population at P1 and 26% at P30, almost all of them located in the posterior 75% of the PE where they comprise 70% of the cell population at some radial positions. Mitotic cells, detected by fluorescent monoclonal antibody R3, are distributed across the entire PE at E13. As the eye grows the mitotic zone occupies a progressively smaller and more distal proportion of the increasing radius; by P5 only the region near the ora serrata is highly active, with some additional mitotic cells trailing into a broad central zone. From P7 to P15 nuclear divisions persist only centrally to generate the youngest uninucleate and binucleate cells. The mouse PE thus shows a pattern of edge-biased interstitial growth (in contrast to amphibians with strict edge growth).

Animals↗
PubMed1987

Growth and development of the mouse retinal pigment epithelium. II. Cell patterning in experimental chimaeras and mosaics.

The retinal pigment epithelium (PE), with pigmentation as a cell-autonomous marker, was analyzed in three types of mice: congenic pigmented----albino chimaeras, X-inactivation mosaics (Cattanach's translocation), and mosaics homozygous for the pink-eyed unstable mutation, which contain rare fully pigmented cells. In 10 chimaeric and 34 X-inactivation eyes, the proportionate mix in the right and left eyes of an individual animal was similar, the mix was approximately constant in all parts of a given eye, average patch size was larger toward the periphery of the PE, and peripheral patches tended to be elongated in the radial dimension. In all 44 whole mounts from pink-eyed unstable mutants, patches of 1-12 pigmented cells, each representing a single clone, were scattered throughout the PE; they tended to be larger with increasing distance from the optic nerve head. The collective data are consistent with significant cell mixing prior to specification of the two eye fields, during early organ-forming stages, and during later development of the PE. The tendency of peripheral patches to orient radially reflects the edge-biased pattern of cell proliferation in the PE. Cell mixing appears to be more prominent posteriorly in the PE sheet; growth proceeds anteriorly for more generations.

Animals↗
PubMed1987

Peripheral nerve regeneration with entubulation repair: comparison of biodegradeable nerve guides versus polyethylene tubes and the effects of a laminin-containing gel.

These experiments present quantitative data concerning peripheral nerve regeneration in vivo. We used entubulation repair as a model to compare two different types of tubular prostheses, one nonbiodegradable and the other biodegradable. We modified the microenvironment of the regenerating axons within the tubular prostheses by adding a laminin-containing gel to the interior of the tube at the time of initial implantation. The data demonstrate that specific manipulations to the microenvironment of regenerating peripheral axons have quantitative effects on the rate and extent of nerve regeneration. Such effects were dependent on the composition of the tubular prosthesis and varied according to the survival time of the animals. For instance, the laminin gel within the biodegradable tubes enhanced nerve regeneration at 2 weeks but was inhibitory at 6 weeks. Furthermore, such manipulations may have different effects on the number of myelinated axons found within the regenerating nerve cable versus the number of primary motor and sensory neurons giving rise to such axons. We concluded that: the presence of a laminin-containing gel significantly increased the initial rate at which axons from primary sensory and motor neurons cross a transection site; an initial delay in axonal outgrowth at early time points did not necessarily predict diminished outgrowth at later times; and because of the potential for axonal branching the number of myelinated axons found in the midportion of a tubular prosthesis did not always correlate with the number of primary motor and sensory neurons which gave rise to those axons.

Animals↗