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Biomedical subjects

C Logan

Publications and source records attributed to C Logan.

At least 19 recordsLinked to original sources
PubMed1999

Modulation of EphA receptor function by coexpressed ephrinA ligands on retinal ganglion cell axons.

The Eph family is thought to exert its function through the complementary expression of receptors and ligands. Here, we show that EphA receptors colocalize on retinal ganglion cell (RGC) axons with EphA ligands, which are expressed in a high-nasal-to-low-temporal pattern. In the stripe assay, only temporal axons are normally sensitive for repellent axon guidance cues of the caudal tectum. However, overexpression of ephrinA ligands on temporal axons abolishes this sensitivity, whereas treatment with PI-PLC both removes ephrinA ligands from retinal axons and induces a striped outgrowth of formerly insensitive nasal axons. In vivo, retinal overexpression of ephrinA2 leads to topographic targeting errors of temporal axons. These data suggest that differential ligand expression on retinal axons is a major determinant of topographic targeting in the retinotectal projection.

Animals↗
PubMed1999

Abnormal anteroposterior and dorsoventral patterning of the limb bud in the absence of retinoids.

We describe here how the early limb bud of the quail embryo develops in the absence of retinoids, including retinoic acid. Retinoid-deficient embryos develop to about stage 20/21, thus allowing patterns of early gene activity in the limb bud to be readily examined. Genes representing different aspects of limb polarity were analysed. Concerning the anteroposterior axis, Hoxb-8 was up-regulated and its border was shifted anteriorly whereas shh and the mesodermal expression of bmp-2 were down-regulated in the absence of retinoids. Concerning the apical ectodermal genes, fgf-4 was down-regulated whereas fgf-8 and the ectodermal domain of bmp-2 were unaffected. Genes involved in dorsoventral polarity were all disrupted. Wnt-7a, normally confined to the dorsal ectoderm, was ectopically expressed in the ventral ectoderm and the corresponding dorsal mesodermal gene Lmx-1 spread into the ventral mesoderm. En-1 was partially or completely absent from the ventral ectoderm. These dorsoventral patterns of expression resemble those seen in En-1 knockout mouse limb buds. Overall, the patterns of gene expression are also similar to the Japanese limbless mutant. These experiments demonstrate that the retinoid-deficient embryo is a valuable tool for dissecting pathways of gene activity in the limb bud and reveal for the first time a role for retinoic acid in the organisation of the dorsoventral axis.

Animals↗
PubMed1999

Sequential roles for Fgf4, En1 and Fgf8 in specification and regionalisation of the midbrain.

Experiments involving tissue recombinations have implicated both early vertical and later planar signals in the specification and polarisation of the midbrain. Here we investigate the role of fibroblast growth factors in regulating these processes in the avian embryo. We show that Fgf4 is expressed in the notochord anterior to Hensen's node before transcripts for the earliest molecular marker of midbrain tissue in the avian embryo, En1, are detected. The presence of notochord is required for the expression of En1 in neural plate explants in vitro and FGF4 mimics this effect of notochord tissue. Subsequently, a second member of the fibroblast growth factor family, Fgf8, is expressed in the isthmus in a manner consistent with it providing a polarising signal for the developing midbrain. Using a retroviral vector to express En1 ectopically, we show that En1 can induce Fgf8 expression in midbrain and posterior diencephalon. Results of the introduction of FGF8 protein into the anterior midbrain or posterior diencephalon are consistent with it being at least part of the isthmic activity which can repolarise the former tissue and respecify the latter to a midbrain fate. However, the ability of FGF8 to induce expression of genes which have earlier onsets of expression than Fgf8 itself, namely En1 and Pax2, strongly suggests that the normal function of FGF8 is in maintaining patterns of gene expression in posterior midbrain. Finally, we provide evidence that FGF8 also provides mitogenic stimulation during avian midbrain development.

Animals↗
PubMed1998

Tlx-1 and Tlx-3 homeobox gene expression in cranial sensory ganglia and hindbrain of the chick embryo: markers of patterned connectivity.

Recent evidence suggests that in vertebrates the formation of distinct neuronal cell types is controlled by specific families of homeodomain transcription factors. Furthermore, the expression domains of a number of these genes correlates with functionally integrated neuronal populations. We have isolated two members of the divergent T-cell leukemia translocation (HOX11/Tlx) homeobox gene family from chick, Tlx-1 and Tlx-3, and show that they are expressed in differentiating neurons of both the peripheral and central nervous systems. In the peripheral nervous system, Tlx-1 and Tlx-3 are expressed in overlapping domains within the placodally derived components of a number of cranial sensory ganglia. Tlx-3, unlike Tlx-1, is also expressed in neural crest-derived dorsal root and sympathetic ganglia. In the CNS, both genes are expressed in longitudinal columns of neurons at specific dorsoventral levels of the hindbrain. Each column has distinct anterior and/or posterior limits that respect inter-rhombomeric boundaries. Tlx-3 is also expressed in D2 and D3 neurons of the spinal cord. Tlx-1 and Tlx-3 expression patterns within the peripheral and central nervous systems suggest that Tlx proteins may be involved not only in the differentiation and/or survival of specific neuronal populations but also in the establishment of neuronal circuitry. Furthermore, by analogy with the LIM genes, Tlx family members potentially define sensory columns early within the developing hindbrain in a combinatorial manner.

Amino Acid Sequence↗
PubMed1998

Malicious paraquat poisoning in Oklahoma dogs.

Paraquat is a restricted use herbicide which is extremely toxic to companion animals when ingested. This report details one incident of malicious poisoning involving 6 dogs. All dogs were from the same geographic area, and 5 had pulmonary and renal lesions consistent with paraquat toxicosis. Diagnosis was initiated by a modified dithionite spot test on vomitus from 1 dog. Subsequent tissue paraquat levels ranged from non-detectable to 1 ppm.

Animals↗
PubMed1997

The role of Engrailed in establishing the dorsoventral axis of the chick limb.

Expression and mutation analyses in mice suggest that the homeobox-containing gene Engrailed (En) plays a role in dorsoventral patterning of the limb. During the initial stages of limb bud outgrowth, En-1 mRNA and protein are uniformly distributed throughout the ventral limb bud ectoderm. Limbs of En-1(-/-) mice display a double dorsal phenotype suggesting that normal expression of En-1 in the ventral ectoderm is required to establish and/or maintain ventral limb characteristics. Loss of En-1 function also results in ventral expansion of the apical ectodermal ridge (AER), suggesting that En-1 is also required for proper formation of the AER. To further investigate the role En plays in dorsoventral patterning and AER formation, we have used the replication competent retroviral vector, RCAS, to mis-express mouse En-1 in the early chick limb bud. We show that ectopic En-1 expression in dorsal ectoderm is sufficient to repress the endogenous expression of the dorsal ectodermal marker Wnt7a, with a resultant decrease in Lmx1 expression in underlying dorsal mesenchyme. Furthermore, the AER is disrupted morphologically and the expression patterns of the AER signalling molecules Fgf-8 and Fgf-4 are altered. Consistent with recent evidence that there is a reciprocal interaction between signalling molecules in the dorsal ectoderm, AER, and zone of polarising activity (ZPA), loss of Wnt7a, Fgf-8 and Fgf-4 expression leads to a decrease in expression of the signalling molecule Shh in the ZPA. These results strongly support the idea that, in its normal domain of expression, En-1 represses Wnt7a-mediated dorsal differentiation by limiting the expression of Wnt7a to the dorsal ectoderm. Furthermore, our results provide additional evidence that En-1 is involved in AER formation and suggest that En-1 may act to define ventral ectodermal identity.

Alpharetrovirus↗
PubMed1996

Rostral optic tectum acquires caudal characteristics following ectopic engrailed expression.

BACKGROUND: Expression of the homeobox-containing gene Engrailed (En) in an increasing rostral-to-caudal gradient in the dorsal mesencephalon is the earliest known marker for polarity of the chick optic tectum. In heterotopic transplantation experiments, En protein expression correlates well with the subsequent gradient of cytoarchitecture as well as the pattern of retinotectal projections. The En gradient also correlates with the expression of two putative retinal axon-guidance molecules, RAGS and ELF-1, which are Eph-like receptor tyrosine kinase ligands that may function in the establishment of retinotopic projections by excluding temporal axons from the caudal tectum. RESULTS: To examine the function of En in determining tectal polarity, we used the replication-competent retroviral vector RCAS to misexpress mouse En-1 throughout the chick tectal primordium. Our results show that the rostral portion of the tectum adopts a caudal phenotype: the gradient of cytoarchitectonic differentiation is abolished, and the molecular markers RAGS and ELF-1 are strongly expressed rostrally. In addition, cell membranes from rostral tectum of RCAS En-1-infected embryos preferentially repel temporal axons in in vitro membrane stripe assays. CONCLUSIONS: These results are consistent with a role for En in determining rostrocaudal polarity of the developing tectum. The demonstration that both RAGS and ELF-1 are upregulated following En misexpression provides a molecular basis for understanding the previous observation, also based on retrovirus-mediated En misexpression, that nasal axons form ectopic connections in rostral tectum, from which temporal axons are excluded.

Animals↗
PubMed1993

Regional assignment of the human homeobox-containing gene EN1 to chromosome 2q13-q21.

The human homeobox-containing genes EN1 and EN2 are closely related to the Drosophila pattern formation gene engrailed (en), which may be important in brain development, as shown by gene expression studies during mouse embryogenesis. Here, we have refined the localization of EN1 to human chromosome 2q13-q21 using a mapping panel of rodent/human cell hybrids containing different regions of chromosome 2 and a lymphoblastoid cell line with an interstitial deletion, del(2)(q21-q23.2). This regional assignment of EN1 increases to 22 the number of currently known genes on human chromosome 2q that have homologs on the proximal region of mouse chromosome 1.

Animals↗
PubMed1993

Two enhancer regions in the mouse En-2 locus direct expression to the mid/hindbrain region and mandibular myoblasts.

An En-2/lacZ gene fusion containing 9.5 kb of En-2 genomic DNA was capable of directing lacZ expression in an En-2-specific manner both temporally and spatially during embryogenesis and in the adult. lacZ expression was confined in the embryo to cells within the mid/hindbrain and mandibular arch regions and in the adult to cells of the molecular and granular layers of the cerebellum, and within the pons and colliculi regions. Interestingly, in the adult, transgene expression patterns within the cerebellum in two lines appeared to mark distinct anterior-posterior compartments. Analysis of the expression pattern of this transgene, in fetal and adult mice lacking a functional En-2 protein, provided evidence that the En-2 gene in mouse is not autoregulated. Deletion analysis of the En-2 genomic region and the use of a heterologous promoter identified two enhancer-containing regions of 1.5 and 1.0 kb in length, 5' of the transcribed sequences, which independently directed expression in the embryo to either the mid/hindbrain region or mandibular myoblasts, respectively. The 1.5 kb fragment contains the most anterior neural enhancer and the 1.0 kb fragment, the earliest myogenic enhancer thus far characterized. These En-2-specific regulatory regions can now be used in a biochemical analysis to identify proteins important in anterior-posterior patterning of the vertebrate CNS and in the specification of muscle identity as well as in a mutational analysis to direct expression of other developmentally important genes to these regions.

Animals↗
PubMed1992

Cloning and sequence comparison of the mouse, human, and chicken engrailed genes reveal potential functional domains and regulatory regions.

We have isolated and characterized genomic DNA clones for the human and chicken homologues of the mouse En-1 and En-2 genes and determined the genomic structure and predicted protein sequences of both En genes in all three species. Comparison of these vertebrate En sequences with the Xenopus En-2 [Hemmati-Brivanlou et al., 1991) and invertebrate engrailed-like genes showed that the two previously identified highly conserved regions within the En protein ]reviewed in Joyner and Hanks, 1991] can be divided into five distinct subregions, designated EH1 to EH5. Sequences 5' and 3' to the predicted coding regions of the vertebrate En genes were also analyzed in an attempt to identify cis-acting DNA sequences important for the regulation of En gene expression. Considerable sequence similarity was found between the mouse and human homologues both within the putative 5' and 3' untranslated as well as 5' flanking regions. Between the mouse and Xenopus En-2 genes, shorter stretches of sequence similarity were found within the 3' untranslated region. The 5' untranslated regions of the mouse, chicken and Xenopus En-2 genes, however, showed no similarly conserved stretches. In a preliminary analysis of the expression pattern of the human En genes, En-2 protein and RNA were detected in the embryonic and adult cerebellum respectively and not in other tissues tested. These patterns are analogous to those seen in other vertebrates. Taken together these results further strengthen the suggestion that En gene function and regulation has been conserved throughout vertebrate evolution and, along with the five highly conserved regions within the En protein, raise an interesting question about the presence of conserved genetic pathways.

Amino Acid Sequence↗
PubMed1992

Soft drink consumption and urinary stone recurrence: a randomized prevention trial.

The object of this study was to determine if a strong association between soft drink (soda) consumption and recurrence of urinary stone disease, found in an earlier case-control study of adult males, had a causal component. The study sample consisted of 1009 male subjects, who completed an episode of urinary stone disease, who were aged 18-75 at that time, and who reported consuming at least 160 ml per day of soft drinks. Half of the subjects were randomized to refrain from consuming soft drinks, while the remaining subjects served as controls. The intervention group had an observed 6.4% advantage in actuarial 3 yr freedom from recurrence (p = 0.023 one-sided) over the control group. One important secondary finding was that for those who reported at the time of the index stone that their most consumed drink was acidified by phosphoric acid but not citric acid, the experimental group had a 15% higher 3 yr recurrence-free rate than the controls, p = 0.002, while for those who reported at the time of the index stone that their most consumed drink was acidified by citric acid with or without phosphoric acid, the experimental group had a similar 3 yr recurrence-free rate to the controls, p = 0.55. This interaction was significant, p = 0.019.

Actuarial Analysis↗
PubMed1989

Chromosomal localization of the human homeo box-containing genes, EN1 and EN2.

The human homologs of the mouse homeo box-containing genes, En-1 and En-2, which show homology to the Drosophila engrailed gene, have been isolated. The human EN1 gene was mapped to chromosome 2 by analysis of mouse-human somatic cell hybrids. The human EN2 gene was localized to chromosome 7, 7q32-7qter, by analysis of rodent-human somatic cell hybrids and cell lines carrying portions of chromosome 7.

Animals↗