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Biomedical subjects

D G Wilkinson

Publications and source records attributed to D G Wilkinson.

At least 19 recordsLinked to original sources
PubMed2003

A randomised placebo controlled study to assess the effects of cholinergic treatment on muscarinic receptors in Alzheimer's disease.

OBJECTIVE: To determine the effects of cholinergic treatment on the muscarinic receptor in patients with Alzheimer's disease. METHODS: 12 patients with mild to moderate Alzheimer's disease and six controls were studied. The patients underwent ADAS-COG psychometric assessment and SPECT brain imaging with (123)I quinuclidinyl benzilate (QNB), to demonstrate the postsynaptic muscarinic M1 receptor, before being randomised in a double blind study to receive either an acetylcholinesterase inhibitor (donepezil) or placebo for four months. Following this, the ADAS-COG and the (123)I-QNB receptor scan were repeated. The controls were imaged on one occasion only. All image analyses were undertaken using SPM99. RESULTS: (123)I-QNB imaging showed a significant relation between baseline psychometric impairment and deficits on scanning. Both placebo and actively treated groups had reductions in (123)I-QNB uptake. Greater reductions in receptor binding were demonstrated in the placebo group than in those receiving active treatment. Intraindividual reproducibility of the (123)I-QNB imaging technique appeared highly robust. CONCLUSIONS: The results suggest that (123)I-QNB uptake is better preserved in Alzheimer's disease patients on cholinergic treatment than on placebo. Cholinergic treatment may play a neuroprotective role. Sequential (123)I-QNB imaging seems to be a powerful tool in monitoring the response of these receptors to disease modifying treatments.

Aged↗
PubMed2002

Galantamine provides broad benefits in patients with 'advanced moderate' Alzheimer's disease (MMSE < or = 12) for up to six months.

We investigated whether galantamine (Reminyl), a cholinergic agent with a dual mode of action for the treatment of mild to moderate Alzheimer's disease (AD), would benefit patients with more advanced illness. We performed a post hoc analysis on pooled data from four pivotal studies in patients with 'advanced moderate' AD: baseline Mini-Mental State Evaluation (MMSE) scores < or = 12 (range 10-12; mean MMSE score 11) or Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores >30 (range 31-69; mean ADAS-cog score 39). Over 5-6 months, cognitive abilities were improved with galantamine versus placebo (p<0.001; mean treatment difference 6.5 points). At 6 months, galantamine benefited functional abilities (p<0.001 vs placebo). The first quartile of galantamine patients improved over baseline by 10.5 ADAS-cog points. Cognitive and functional abilities were maintained around baseline; behavioural symptoms were delayed. Over 6 months, galantamine provided a broad spectrum of benefits to patients with 'advanced moderate' AD.

Aged↗
PubMed2001

The zebrafish Hairy/Enhancer-of-split-related gene her6 is segmentally expressed during the early development of hindbrain and somites.

Several vertebrate genes of the Hairy/Enhancer-of-split (HES) family are involved in paraxial mesoderm segmentation and intersomitic boundary establishment/maintenance. Here, we show that the zebrafish hairy-related gene, her6, highly homologous to the mammalian and chicken HES-1 genes, is expressed in the posterior part of each segmented somite and in stripes in the anterior presomitic mesoderm (PSM), and also in a dynamic, segmentally restricted pattern during hindbrain segmentation, with all rhombomeres expressing her6 at different time points and at different levels.

Amino Acid Sequence↗
PubMed2001

Screening from a subtracted embryonic chick hindbrain cDNA library: identification of genes expressed during hindbrain, midbrain and cranial neural crest development.

The vertebrate hindbrain is segmented into a series of transient structures called rhombomeres. Despite knowing several factors that are responsible for the segmentation and maintenance of the rhombomeres, there are still large gaps in understanding the genetic pathways that govern their development. To find previously unknown genes that are expressed within the embryonic hindbrain, a subtracted chick hindbrain cDNA library has been made and 445 randomly picked clones from this library have been analysed using whole mount in situ hybridisation. Thirty-six of these clones (8%) display restricted expression patterns within the hindbrain, midbrain or cranial neural crest and of these, twenty-two are novel and eleven encode peptides that correspond to or are highly related to proteins with previously uncharacterised roles during early neural development. The large proportion of genes with restricted expression patterns and previously unknown functions in the embryonic brain identified during this screen provides insights into the different types of molecules that have spatially regulated expression patterns in cranial neural tissue.

Amino Acid Sequence↗
PubMed2001

Multiple roles of EPH receptors and ephrins in neural development.

The control of cell movement during development is essential for forming and stabilizing the spatial organization of tissues and cell types. During initial steps of tissue patterning, distinct regional domains or cell types arise at appropriate locations, and the movement of cells is constrained in order to maintain spatial relationships during growth. In other situations, the guidance of migrating cells or neuronal growth cones to specific destinations underlies the establishment or remodeling of a pattern. Eph receptor tyrosine kinases and their ephrin ligands are key players in controlling these cell movements in many tissues and at multiple stages of patterning.

Animals↗
PubMed2000

Roles of Eph receptors and ephrins in segmental patterning.

Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins, have key roles in patterning and morphogenesis. Interactions between these molecules are promiscuous, but largely fall into two groups: EphA receptors bind to glycosylphosphatidyl inositol-anchored ephrin-A ligands, and EphB receptors bind to transmembrane ephrin-B proteins. Ephrin-B proteins transduce signals, such that bidirectional signalling can occur upon interaction with the Eph receptor. In many tissues, there are complementary and overlapping expression domains of interacting Eph receptors and ephrins. An important role of Eph receptors and ephrins is to mediate cell contact-dependent repulsion, and this has been implicated in the pathfinding of axons and neural crest cells, and the restriction of cell intermingling between hindbrain segments. Studies in an in vitro system show that bidirectional activation is required to prevent intermingling between cell populations, whereas unidirectional activation can restrict cell communication via gap junctions. Recent work indicates that Eph receptors can also upregulate cell adhesion, but the biochemical basis of repulsion versus adhesion responses is unclear. Eph receptors and ephrins have thus emerged as key regulators that, in parallel with cell adhesion molecules, underlie the establishment and maintenance of patterns of cellular organization.

Animals↗
PubMed2000

Topographic mapping: organising by repulsion and competition?

The establishment of topographic maps of neuronal connections is believed to involve graded repulsion mediated by EphA receptors and ephrin-A ligands. Gene knockouts show that ephrin-A ligands do indeed have a crucial role in mapping, and that mechanisms in addition to graded repulsion must also be at work.

Animals↗
PubMed2000

Donepezil in Alzheimer's disease: eighteen month results from Southampton Memory Clinic.

The objective of this study was to assess the efficacy of donepezil in patients with mild to moderate Alzheimer's disease (AD) in clinical practice. This was an open-label study in which patients were referred to an elderly mental health clinic in Southampton, UK. Eighty patients with mild to moderate AD received 5 mg/day donepezil for the first 4 weeks, after which, if tolerated, the dose was increased to 10 mg/day. Efficacy and safety assessments were carried out every 3 months. Efficacy was assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Neuropsychiatric Inventory-carer Distress Scale (NPI-D). Mean improvements from baseline were observed at the 3-month assessment on all four efficacy measures. At 3 months, 39% of patients showed an improvement of at least 4 points on the ADAS-cog, and 37% of patients had improved by 4 points or more on the NPI. In those patients who showed improvement and were maintained on donepezil, improvements were sustained for 18 months on the MMSE and NPI, 15 months on the NPI-D, and for 6 months on the ADAS-cog. Six per cent of patients discontinued medication due to adverse events. In a typical clinical practice setting, patients with mild to moderate AD tolerated donepezil well. Clinically meaningful improvements in cognitive function and a reduction in neuropsychiatric symptoms were demonstrated in nearly 40% of patients with associated reduction in carer distress. Continued benefit was seen for up to 18 months in the selected group of patients who initially responded in treatment.

Adult↗
PubMed2000

Eph receptors and ephrins: regulators of guidance and assembly.

Recent advances have started to elucidate the developmental functions and biochemistry of Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins. Interactions between these molecules are promiscuous, but they largely fall into two groups: EphA receptors bind to GPI-anchored ephrin-A ligands, while EphB receptors bind to ephrin-B proteins that have a transmembrane and cytoplasmic domain. Remarkably, ephrin-B proteins transduce signals, such that bidirectional signaling can occur upon interaction with Eph receptor. In many tissues, specific Eph receptors and ephrins have complementary domains, whereas other family members may overlap in their expression. An important role of Eph receptors and ephrins is to mediate cell-contact-dependent repulsion. Complementary and overlapping gradients of expression underlie establishment of a topographic map of neuronal projections in the retinotectal system. Eph receptors and ephrins also act at boundaries to channel neuronal growth cones along specific pathways, restrict the migration of neural crest cells, and via bidirectional signaling prevent intermingling between hindbrain segments. Intriguingly, Eph receptors and ephrins can also trigger an adhesive response of endothelial cells and are required for the remodeling of blood vessels. Biochemical studies suggest that the extent of multimerization of Eph receptors modulates the cellular response and that the actin cytoskeleton is one major target of the intracellular pathways activated by Eph receptors. Eph receptors and ephrins have thus emerged as key regulators of the repulsion and adhesion of cells that underlie the establishment, maintenance, and remodeling of patterns of cellular organization.

Animals↗
PubMed2000

Molecular control of neural crest formation, migration and differentiation.

Induction, migration and differentiation of the neural crest are crucial for the development of the vertebrate embryo, and elucidation of the underlying mechanisms remains an important challenge. In the past year, a novel signal regulating the formation of neural crest cells has been identified, and advances have been made in uncovering roles for bone morphogenetic protein signals and for a transcription factor in the onset of neural crest migration. There have been new insights into the migration and plasticity of branchial neural crest cells. Important progress has been made in dissecting the roles of bone morphogenetic protein, Wnt and Notch signalling systems and their associated downstream transcription factors in the control of neural crest cell differentiation.

Animals↗
PubMed2000

Control of cell behaviour by signalling through Eph receptors and ephrins.

Eph receptor tyrosine kinases and ephrins mediate contact-dependent cell interactions that regulate the repulsion and adhesion mechanisms involved in the guidance and assembly of cells. Recent work has revealed a role of overlapping Eph receptor and ephrin expression in modulating neuronal growth cone repulsion, and has shown that bidirectional activation restricts intermingling and communication between cell populations. In addition, progress has been made in understanding how Eph receptors and ephrins control cell adhesion.

Animals↗
PubMed1999

Sin1: an evolutionarily conserved component of the eukaryotic SAPK pathway.

The fission yeast Sty1/Spc1 mitogen-activated protein (MAP) kinase is a member of the eukaryotic stress-activated MAP kinase (SAPK) family. We have identified a protein, Sin1, that interacts with Sty1/Spc1 which is a member of a new evolutionarily conserved gene family. Cells lacking Sin1 display many, but not all, of the phenotypes of cells lacking the Sty1/Spc1 MAP kinase including sterility, multiple stress sensitivity and a cell-cycle delay. Sin1 is phosphorylated after stress but this is not Sty1/Spc1-dependent. Importantly, Sin1 is not required for activation of Sty1/Spc1 but is required for stress-dependent transcription via its substrate, Atf1. We find that in the absence of Sin1, Sty1/Spc1 appears to translocate to the nucleus but Atf1 is not fully phosphorylated and becomes unstable in response to environmental stress. Sin1 is also required for effective transcription via the AP-1 factor Pap1 but does not prevent its nuclear translocation. Remarkably chimaeric fusions of sin1 with chicken sin1 sequences rescue loss of sin1 function. We conclude that Sin1 is a novel component of the eukaryotic SAPK pathway.

Acetyltransferases↗
PubMed1999

The role of kreisler in segmentation during hindbrain development.

The mouse kreisler gene is expressed in rhombomeres (r) 5 and 6 during neural development and kreisler mutants have patterning defects in the hindbrain that are not fully understood. Here we analyzed this phenotype with a combination of genetic, molecular, and cellular marking techniques. Using Hox/lacZ transgenic mice as reporter lines and by analyzing Eph/ephrin expression, we have found that while r5 fails to form in these mice, r6 is present. This shows that kreisler has an early role in the formation of r5. We also observed patterning defects in r3 and r4 that are outside the normal domain of kreisler expression. In both heterozygous and homozygous kreisler embryos some r5 markers are induced in r3, suggesting that there is a partial change in r3 identity that is not dependent upon the loss of r5. To investigate the cellular character of r6 in kreisler embryos we performed heterotopic grafting experiments in the mouse hindbrain to monitor its mixing properties. Control experiments revealed that cells from even- or odd-numbered segments only mixed freely with themselves, but not with cells of opposite character. Transposition of cells from the r6 territory of kreisler mutants reveals that they adopt mature r6 characteristics, as they freely mix only with cells from even-numbered rhombomeres. Analysis of Phox2b expression shows that some aspects of later neurogenesis in r6 are altered, which may be associated with the additional roles of kreisler in regulating segmental identity. Together these results suggest that the formation of r6 has not been affected in kreisler mutants. This analysis has revealed phenotypic and mechanistic differences between kreisler and its zebrafish equivalent valentino. While valentino is believed to subdivide preexisting segmental units, in the mouse kreisler specifies a particular segment. The formation of r6 independent of r5 argues against a role of kreisler in prorhombomeric segmentation of the mouse hindbrain. We conclude that the mouse kreisler gene regulates multiple steps in segmental patterning involving both the formation of segments and their A-P identity.

Animals↗
PubMed1999

Eph receptors and ephrins restrict cell intermingling and communication.

Eph proteins are receptors with tyrosine-kinase activity which, with their ephrin ligands, mediate contact-dependent cell interactions that are implicated in the repulsion mechanisms that guide migrating cells and neuronal growth cones to specific destinations. Ephrin-B proteins have conserved cytoplasmic tyrosine residues that are phosphorylated upon interaction with an EphB receptor, and may transduce signals that regulate a cellular response. Because Eph receptors and ephrins have complementary expression in many tissues during embryogenesis, bidirectional activation of Eph receptors and ephrin-B proteins could occur at interfaces of their expression domains, for example at segment boundaries in the vertebrate hindbrain. Previous work has implicated Eph receptors and ephrin-B proteins in the restriction of cell intermingling between hindbrain segments. We therefore analysed whether complementary expression of Eph receptors and ephrins restricts cell intermingling, and whether this requires bidirectional or unidirectional signalling. Here we report that bidirectional but not unidirectional signalling restricts the intermingling of adjacent cell populations, whereas unidirectional activation is sufficient to restrict cell communication through gap junctions. These results reveal that Eph receptors and ephrins regulate two aspects of cell behaviour that can stabilize a distinct identity of adjacent cell populations.

Animals↗
PubMed1999

In vivo cell sorting in complementary segmental domains mediated by Eph receptors and ephrins.

The restriction of intermingling between specific cell populations is crucial for the maintenance of organized patterns during development. A striking example is the restriction of cell mixing between segments in the insect epidermis and the vertebrate hindbrain that may enable each segment to maintain a distinct identity. In the hindbrain, this is a result of different adhesive properties of odd- and even-numbered segments (rhombomeres), but an adhesion molecule with alternating segmental expression has not been found. However, blocking experiments suggest that Eph-receptor tyrosine kinases may be required for the segmental restriction of cells. Eph receptors and their membrane-bound ligands, ephrins, are expressed in complementary rhombomeres and, by analogy with their roles in axon pathfinding, could mediate cell repulsion at boundaries. Remarkably, transmembrane ephrins can themselves transduce signals, raising the possibility that bi-directional signalling occurs between adjacent ephrin- and Eph-receptor-expressing cells. We report here that mosaic activation of Eph receptors leads to sorting of cells to boundaries in odd-numbered rhombomeres, whereas mosaic activation of ephrins results in sorting to boundaries in even-numbered rhombomeres. These data implicate Eph receptors and ephrins in the segmental restriction of cell intermingling.

Animals↗
PubMed1999

Comparative analysis of embryonic gene expression defines potential interaction sites for Xenopus EphB4 receptors with ephrin-B ligands.

The Eph family of receptor tyrosine kinases and their ligands, the ephrins, act as signaling molecules regulating the migratory behavior of neurons and neural crest cells, and are implicated in tissue patterning, blood vessel formation, and tumorigenesis. On the basis of structural similarities and overlapping binding specificities, Eph receptors as well as their ligands can be divided into A and B subfamilies with orthologues found in all vertebrates. We describe here the isolation of cDNAs encoding Xenopus EphB4 receptors and show that embryonic expression is prominently associated with the developing vasculature, newly forming somites, the visceral arches, and non-neuronal tissues of the embryonic head. In a screen to identify potential ligands for EphB4 in Xenopus embryos, we isolated cDNAs for the Xenopus ephrin-B2 and -B3, which demonstrates that the Xenopus genome harbors genes encoding orthologues to all three currently known mammalian ephrin-B genes. We next performed in situ hybridizations to identify tissues and organs where EphB4 receptors may encounter ephrin-B ligands during embryonic development. Our analysis revealed distinct, but overlapping patterns of ephrin-B gene expression. Interestingly, each ephrin-B ligand displayed expression domains either adjacent to or within EphB4-expressing tissues. These findings indicate that EphB4 receptors may interact in vivo with multiple B-class ephrins. The expression patterns also suggest that EphB4 receptors and their ligands may be involved in visceral arch formation, somitogenesis, and blood vessel development.

Alleles↗