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R W Williams

Publications and source records attributed to R W Williams.

At least 55 records · Page 3Linked to original sources
PubMed1999

A new surgery for congenital nystagmus: effects of tenotomy on an achiasmatic canine and the role of extraocular proprioception.

PURPOSE: Human eye-movement recordings have documented that surgical treatment of congenital nystagmus (CN) also produces a broadening of the null zone and changes in foveation that allow increased acuity. We used the achiasmatic Belgian sheepdog, a spontaneously occurring animal model of human CN and see-saw nystagmus (SSN), to test the hypothesis that changes induced by surgical interruption of the extraocular muscle afference without a change in muscle-length tension could damp both oscillations. METHODS: An achiasmatic dog with CN and SSN underwent videotaping and infrared oculography in a sling apparatus and head restraints before and after all extraocular muscles (stage 1: 4 horizontal rectus muscles and stage 2 [4 months later]: 4 vertical rectus muscles and 4 oblique muscles) were surgically tenotomized and immediately reattached at their original insertions. RESULTS: The dog had immediate and persistent visible, behavioral, and oculographic changes after each stage of this new procedure. These included damped CN and SSN, increased ability to maintain fixation, and increased periods of maintaining the target image on the area centralis over a broad range of gaze angles. CONCLUSIONS: Severing and reattaching the tendons of the extraocular muscles affect some as-yet-unknown combination of central nervous system processes producing the above results. This new procedure may prove effective in patients with CN with either no null, a null at primary position, or a time-varying null (due to asymmetric, (a)periodic, alternating nystagmus). We infer from our results in an achiasmatic dog that tenotomy is the probable cause of the damping documented in human CN after Anderson-Kestenbaum procedures and should also damp CN and SSN in achiasma in humans. It may also prove useful in acquired nystagmus to reduce oscillopsia. The success of tenotomy in damping nystagmus in this animal suggests that the proprioceptive feedback loop has a more important role in ocular-motor control than has been appreciated. Finally, we propose a modified bimedial recession procedure, on the basis of the damping effects of tenotomy.

Animals↗
PubMed1999

Genetic and physical characterization of a region of Arabidopsis chromosome 1 containing the CLAVATA1 gene.

With the advance of Arabidopsis as a model system for understanding plant genetics, development and biochemistry, a detailed description of the genome is necessary. As such, focused projects are underway to map and sequence the Arabidopsis nuclear genome. We have characterized a region of chromosome 1, surrounding the CLAVATA1 (CLV1) locus. Three (RFLP) clones were mapped relative to clv1-1, and were used to construct an ca. 700 kb yeast artificial chromosome (YAC) contig. Three cosmids spanning the CLV1 locus were analyzed and ca. 24 kb of genomic DNA was sequenced, including a continuous stretch of 18 kb. In addition to generating clones in this region of chromosome 1, we have analyzed the size, spacing and organization of several contiguous genes.

Arabidopsis↗
PubMed1999

A quantitative genetic analysis of slow-wave sleep and rapid-eye movement sleep in CXB recombinant inbred mice.

Various inbred strains of mice show different daily amounts of slow-wave sleep (SWS) and rapid-eye movement sleep (REMS), suggesting the possibility of genetic influences on sleep propensity. Previous work by others studying the spontaneous sleep patterns of seven strains of CXB recombinant inbred (RI) mice suggested several candidate quantitative trait loci (QTLs) associated with variation in REMS. Extending this approach, we evaluated the sleep patterns of 13 CXB RI strains and conducted linkage analyses based on 223 discrete informative loci. The probability density distribution of light phase REMS for the CXB RI strains showed deflections that correspond approximately to the parental phenotypes. This type of pattern is consistent with the presence of a low number of major effect quantitative trait loci. Regions of chromosomes 4, 16, and 17 showed provisional linkage to strain variation in REMS. The distribution of loci further suggested that dark phase and light phase REMS may be regulated by different genetic factors. Probabilities of linkage were not sufficient for declaration of a quantitative trait locus for REMS but were sufficient to warrant further analysis either with additional RI strains or with F2 panels.

Animals↗
PubMed1999

A quantitative genetic analysis of locomotor activity in CXB recombinant inbred mice.

Recent studies have identified genes that influence the length of the circadian period maintained by mice housed under constant lighting conditions. However, a less studied circadian activity variable is the amplitude of daily oscillations in locomotor activity. This parameter reflects spontaneous activity exhibited under standard lighting and housing conditions and, therefore, differs conceptually from assessments of exploratory or open-field activity, voluntary wheel-running, or circadian period during exposure to constant light or constant darkness conditions. We recently observed a greater daily amplitude of oscillation in spontaneous locomotor activity in C57BL/6 mice compared to BALB/cBy mice. To identify genetic loci with potential linkage to circadian variation in the amount of locomotor activity, we measured the spontaneous activity of 13 CXB recombinant inbred (RI) strains of mice. The probability density distributions of locomotor activity phenotypes for the 13 CXB RI strains were consistent with the presence of a low number of major quantitative trait loci affecting this trait. Regions of chromosomes 3, 8, 12, 13, and 19 showed provisional linkage to strain variation in locomotor activity. Probabilities of linkage were not sufficient for declaration of an activity-related quantitative trait locus but were sufficient to warrant further analysis either with additional RI strains or with F2 panels.

Animals↗
PubMed1999

A quantitative genetic analysis of slow-wave sleep in influenza-infected CXB recombinant inbred mice.

Influenza-infected C57BL/6J mice spend increased amounts of time in slow-wave sleep (SWS) during the dark phase of the circadian cycle compared to healthy mice. In contrast, infected BALB/cByJ mice show a normal or reduced time in SWS, particularly during the light phase. To identify genetic loci with linkage to these traits, we measured sleep in 13 CXB recombinant inbred (RI) strains derived from a cross between C57BL/6ByJ and BALB/cByJ mice. The probability density distribution of sleep patterns of influenza-infected CXB RI mice showed modes that correspond roughly with the parental modes during the dark phase of the circadian cycle and are intermediate or C57BL/6-like during the light phase. These patterns are consistent with the presence of a low number of major effect quantitative trait loci (QTLs). Chromosomal regions with provisional association to strain variation in influenza-induced SWS patterns were identified. In particular, a 10- to 12-cM interval on Chr 6 between D6Mit74 and D6Mit188 contains a QTL (LRS = 16.6 at 1 cM proximal to D6Mit316; genomewide p < .05) that influences the SWS response to influenza infection during the light phase. We have provisionally named this QTL Srilp1 (sleep response to influenza, light phase 1). Candidate genes for mediation of this phenotype include Ghrhr (growth hormone releasing hormone receptor), Crhr2 (corticotropin releasing hormone receptor 2), and Cd8a (an epitope on cytotoxic T lymphocytes). Several other intervals achieved suggestive probability scores that are sufficient to warrant further analysis either with additional RI strains or with F2 panels. The analysis also suggests that dark phase and light phase responses are regulated by different genetic factors.

Animals↗
PubMed1999

Mouse models for the analysis of myopia: an analysis of variation in eye size of adult mice.

PURPOSE: To assess the relative importance of genetic and environmental factors that modulate eye growth, eyes, lenses, and retinas of 507 mice belonging to 50 strains were measured. METHODS: Mice of both sexes and a wide range of ages (27 to 526 days) were perfused for electron microscopy and eyes, lenses, and retinas were dissected and measured. Our uniform fixation protocol was shown to cause a weight loss of 4 to 6%. Multiple linear regression methods were used to explore relations between eye and lens weight, retinal area, age, sex, body and brain weight, and retinal ganglion cell number. RESULTS: The eye and lens of mice continue to grow long after sexual maturity is reached at 40 to 60 days of age. The pace of growth matches the logarithm of age. Despite their smaller bodies, females have eyes as large as those of males. The correlation of eye weight to brain weight is remarkably low (r = 0.19), whereas that to retinal area is high (r = 0.86). Surprisingly, the correlation between lens weight and the size of the posterior segment (eye minus lens weight) is only 0.5 to 0.6, and ratios of these parameters are highly variable. Heritability of all traits is between 25 to 50%. CONCLUSIONS: The continued growth of eyes in adult mice provides an excellent system to test effects of genetic and molecular manipulations on the development and treatment of myopia. Heritability is sufficiently high to map genes that specifically modulate growth of different parts of the eye.

Age Factors↗
PubMed1999

Eye1 and Eye2: gene loci that modulate eye size, lens weight, and retinal area in the mouse.

PURPOSE: Vision is critically dependent on genetic factors that influence the rate and duration of eye growth. The genetic basis of variation in eye size in mice was explored, and genes that modulate eye weight, lens weight, and retinal area were mapped. METHODS: Eyes of approximately 700 mice were weighed. Data were corrected by regression analysis to eliminate effects of sex, age, and body weight. Interval mapping was used to locate quantitative trait loci (QTLs) using recombinant inbred strains and F2 intercrosses between strains C57BL/6J and DBA/2J. RESULTS: Major QTLs were discovered near the centromere of chromosome 5 (Eye1: genomewide P < 0.005) and on proximal chromosome 17 near the mast cell protease 6 gene (Eye2, P < 0.05). Both QTLs have significant effects on eye size, lens weight, and retinal area. The DBA/2J alleles at Eye1 and Eye2 are partially dominant and increase eye weight by as much as 1.0 mg. Analysis of 183 F2 progeny confirmed and refined the chromosomal assignments of both Eye1 and Eye2. CONCLUSIONS: Eye1 and Eye2 are the first loci known to control normal variation in eye size in any mammal. The hepatic growth factor gene (Hgf), a potent mitogen expressed in the retina, pigment epithelium, and choroid, is a strong candidate for Eye1. The human homolog of Eye2 should map to chromosome 6p, 16q13.3, or 19q13, whereas that of Eye1 should map to 7q.

Animals↗
PubMed1998

Cell production and cell death in the generation of variation in neuron number.

Retinal ganglion cell numbers in adult mice vary from 40,000 to 80, 000. Much of this variation and the prominent bimodality of strain averages are generated by allelic variants at the neuron number control 1 (Nnc1) locus on chromosome 11. The Nnc1 locus may modulate either ganglion cell production or the severity of ganglion cell death. Here we have determined what the relative contributions of these two processes are to variation in adult cell number by estimating total ganglion cell production in 10 strains of mice (A/J, BALB/cJ, BXD32, C57BL/6J, CAST/Ei, CARL/ChGo, CE/J, C3H/HeSnJ, DBA/2J, and LP/J). These strains have adult populations that range from 45,000 to 76,000 (data available at http://qtl.ml.org). We estimated cell production by counting ganglion cell axons after ganglion cell neurogenesis but before the onset of significant cell death. Total cell production ranges from 131,000 to 224,000, and most of the variation in adult ganglion cell number is explained by this significant variation in cell production. In contrast, the percentage of cell death is relatively uniform in most strains (approximately 69% cell loss). The exceptions are BXD32, a strain that has an extremely high adult cell population, and Mus caroli (CARL/ChGo), a wild southeast Asian species that is distantly related to laboratory strains. In BXD32 and M. caroli, approximately 62% of the population dies. Our analysis indicates that substitutions of single alleles at the Nnc1 locus are responsible for production differences of approximately 8000 ganglion cells.

Animals↗
PubMed1998

Natural variation in neuron number in mice is linked to a major quantitative trait locus on Chr 11.

Common genetic polymorphisms-as opposed to rare mutations-generate almost all heritable differences in the size and structure of the CNS. Surprisingly, these normal variants have not previously been mapped or cloned in any vertebrate species. In a recent paper (), we suggested that much of the variation in retinal ganglion cell number in mice, and the striking bimodality of strain averages, are caused by one or two quantitative trait loci (QTLs). To test this idea, and to map genes linked to this variable and highly heritable quantitative trait, we have counted ganglion cells in 38 recombinant inbred strains (BXD and BXH) derived from parental strains that have high and low cell numbers. A genome-wide search using simple and composite interval-mapping techniques revealed a major QTL on chromosome (Chr) 11 in a 3 cM interval between Hoxb and Krt1 (LOD = 6.8; genome-wide p = 0.001) and possible subsidiary QTLs on Chr 2 and Chr 8. The Chr 11 locus, neuron number control 1 (Nnc1), accounts for one third of the genetic variance among BXH strains and more than half of that among BXD strains, but Nnc1 has no known effects on brain weight, eye weight, or total retinal cell number. Three strong candidate genes have been mapped previously to the same region as Nnc1. These genes-Rara, Thra, and Erbb2- encode receptors for retinoic acid, thyroxine, and neuregulin, respectively. Each receptor is expressed in the retina during development, and their ligands affect the proliferation or survival of retinal cells.

Animals↗
PubMed1998

Plant homeobox genes: many functions stem from a common motif.

Homeodomain-containing transcription factors play a variety of important roles in plant, animal, and fungal development. Mutational and evolutionary analysis is beginning to pinpoint specific roles of homeobox genes in plant meristem function. Even though many different plant homeobox genes encode very similar homeodomain sequences, overexpression studies suggest the existence of several levels of regulation that may specify the functions of the different proteins. Recent analysis of the maize Knotted1 gene and its orthologue in barley demonstrates some of these regulatory processes.

Amino Acid Sequence↗
PubMed1998

Three-dimensional structure of HIV-1 Rev protein filaments.

The HIV-1 Rev protein facilitates the export of incompletely spliced and unspliced viral mRNAs from the nucleus. Rev polymerizes into two types of filaments in vitro. In the presence of RNA, Rev forms poorly ordered structures, while in the absence of RNA it polymerizes into regular hollow filaments. We have determined the helical structure of the latter filaments by analysis of cryo-electron micrographs, taking into account STEM measurements of mass-per-unit-length. They are made up of Rev dimers, arranged in a six-start helix, with 31 dimers in 2 turns, a pitch angle of 45 degrees, and an interstrand spacing of 3.8 nm. Three-dimensional reconstruction at 2.1 nm resolution reveals a smooth outer surface and a featured inner surface, with outer and inner diameters of approximately 14.8 and approximately 10.4 nm, respectively. The Rev dimer has a "top-hat" shape with a cylinder approximately 3.2 nm in diameter and approximately 2.2 nm high, pointing inward: the thinner rim areas pack together to form the filament wall. Raman spectroscopy shows polymerized Rev to have approximately 54% alpha-helix and 20-24% beta-sheet content. Electron microdiffraction of aligned filaments reveals a broad meridional reflection at approximately (0.51 nm(-1, suggesting approximate alignment of the alpha-helices with the filament axis. Based on these data, a molecular model for the Rev filament is proposed.

Dimerization↗
PubMed1998

Genetic dissection of retinal development.

Retinal development depends on complex interactions between products of thousands of genes and numerous cellular and environmental factors. We are using novel quantitative genetic methods to map and characterize genes that are responsible for the pervasive quantitative differences in the architecture of the eye and the retina. These genes, known as quantitative trait loci (QTLs), may also determine susceptibility to common eye diseases. To map QTLs that generate variation among normal individuals we have analyzed several traits in a wide variety of mice, including standard inbred strains, recombinant inbred strains, wild mice, F1 hybrids and intercross progeny. Here we review this approach and give three specific examples of how genes with well-defined functions in retinal development are being mapped and characterized.

Animals↗
PubMed1998

The congenital and see-saw nystagmus in the prototypical achiasma of canines: comparison to the human achiasmatic prototype.

We applied new methods for canine eye-movement recording to the study of achiasmatic mutant Belgian Sheepdogs, documenting their nystagmus waveforms and comparing them to humans with either congenital nystagmus (CN) alone or in conjunction with achiasma. A sling apparatus with head restraints and infrared reflection with either earth- or head-mounted sensors were used. Data were digitized for later evaluation. The horizontal nystagmus (1-6 Hz) was similar to that of human CN. Uniocular and disconjugate nystagmus and saccades were recorded. See-saw nystagmus (SSN), not normally seen with human CN, was present in all mutants (0.5-6 Hz) and in the one human achiasmat studied thus far. This pedigree is an animal model of CN and the SSN caused by achiasma or uniocular decussation. Given the finding of SSN in all mutant dogs and in a human, achiasma may be sufficient for the development of congenital SSN and, in human infants, SSN should alert the clinician to the possibility of either achiasma or uniocular decussation. Finally, the interplay of conjugacy and disconjugacy suggests independent ocular motor control of each eye with variable yoking in the dog.

Animals↗
PubMed1998

Multiple modes of cell division control in Arabidopsis flower development.

Control of the pattern of cell divisions is central to plant development. Several different types of control exist: examples include control of overall cell number in floral meristems, control of relative cell numbers in floral whorls, and control of the relative spacing of the cell divisions that establish floral organs. Mutations that change each of these levels of control are described: mutations in the SUPERMAN gene affect relative amounts of cell division in adjacent floral whorls; mutations in the CLAVATA genes affect overall meristematic cell number; and mutations in PERIANTHIA affect the spacing of floral organs.

Arabidopsis↗
PubMed1997

A possible role for kinase-associated protein phosphatase in the Arabidopsis CLAVATA1 signaling pathway.

Continuous growth and development in plants are accomplished by meristems, groups of undifferentiated cells that persist as stem cells and initiate organs. While the structures of the apical and floral meristems in dicotyledonous plants have been well described, little is known about the underlying molecular mechanisms controlling cell proliferation and differentiation in these structures. We have shown previously that the CLAVATA1 (CLV1) gene in Arabidopsis encodes a receptor kinase-like protein that controls the size of the apical and floral meristems. Here, we show that KAPP, a gene encoding a kinase-associated protein phosphatase, is expressed in apical and young floral meristems, along with CLV1. Overexpression of KAPP mimics the clv1 mutant phenotype. Furthermore, CLV1 has kinase activity: it phosphorylates both itself and KAPP. Finally, KAPP binds and dephosphorylates CLV1. We present a model where KAPP functions as a negative regulator of the CLAVATA1 signal transduction pathway.

Arabidopsis↗
PubMed1997

The CLAVATA1 gene encodes a putative receptor kinase that controls shoot and floral meristem size in Arabidopsis.

The shoot apical meristem is responsible for above-ground organ initiation in higher plants, accomplishing continuous organogenesis by maintaining a pool of undifferentiated cells and directing descendant cells toward organ formation. Normally, proliferation and differentiation are balanced, so that the structure and size of the shoot meristem is maintained. However, Arabidopsis plants homozygous for mutations at the CLAVATA1 (CLV1) locus accumulate excess undifferentiated cells. We describe the molecular cloning and expression pattern of the CLV1 gene. It encodes a putative receptor kinase, suggesting a role in signal transduction. The extracellular domain is composed of 21 tandem leucine-rich repeats that resemble leucine-rich repeats found in animal hormone receptors. We provide evidence that CLV1 expression in the inflorescence is specifically associated with meristematic activity.

Amino Acid Sequence↗