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Biomedical subjects

H Marshall

Publications and source records attributed to H Marshall.

At least 37 records · Page 2Linked to original sources
PubMed2001

Independent regulation of initiation and maintenance phases of Hoxa3 expression in the vertebrate hindbrain involve auto- and cross-regulatory mechanisms.

During development of the vertebrate hindbrain, Hox genes play multiple roles in the segmental processes that regulate anteroposterior (AP) patterning. Paralogous Hox genes, such as Hoxa3, Hoxb3 and Hoxd3, generally have very similar patterns of expression, and gene targeting experiments have shown that members of paralogy group 3 can functionally compensate for each other. Hence, distinct functions for individual members of this family may primarily depend upon differences in their expression domains. The earliest domains of expression of the Hoxa3 and Hoxb3 genes in hindbrain rhombomeric (r) segments are transiently regulated by kreisler, a conserved Maf b-Zip protein, but the mechanisms that maintain expression in later stages are unknown. In this study, we have compared the segmental expression and regulation of Hoxa3 and Hoxb3 in mouse and chick embryos to investigate how they are controlled after initial activation. We found that the patterns of Hoxa3 and Hoxb3 expression in r5 and r6 in later stages during mouse and chick hindbrain development were differentially regulated. Hoxa3 expression was maintained in r5 and r6, while Hoxb3 was downregulated. Regulatory comparisons of cis-elements from the chick and mouse Hoxa3 locus in both transgenic mouse and chick embryos have identified a conserved enhancer that mediates the late phase of Hoxa3 expression through a conserved auto/cross-regulatory loop. This block of similarity is also present in the human and horn shark loci, and contains two bipartite Hox/Pbx-binding sites that are necessary for its in vivo activity in the hindbrain. These HOX/PBC sites are positioned near a conserved kreisler-binding site (KrA) that is involved in activating early expression in r5 and r6, but their activity is independent of kreisler. This work demonstrates that separate elements are involved in initiating and maintaining Hoxa3 expression during hindbrain segmentation, and that it is regulated in a manner different from Hoxb3 in later stages. Together, these findings add further strength to the emerging importance of positive auto- and cross-regulatory interactions between Hox genes as a general mechanism for maintaining their correct spatial patterns in the vertebrate nervous system.

Animals↗
PubMed2000

Susceptibility locus for Alzheimer's disease on chromosome 10.

The apolipoprotein E (APOE) gene is the only genetic risk factor that has so far been linked to risk for late-onset Alzheimer's disease (LOAD). However, 50 percent of Alzheimer's disease cases do not carry an APOE4 allele, suggesting that other risk factors must exist. We performed a two-stage genome-wide screen in sibling pairs with LOAD to detect other susceptibility loci. Here we report evidence for an Alzheimer's disease locus on chromosome 10. Our stage one multipoint lod score (logarithm of the odds ratio for linkage/no linkage) of 2.48 (266 sibling pairs) increased to 3.83 in stage 2 (429 sibling pairs) close to D10S1225 (79 centimorgans). This locus modifies risk for Alzheimer's disease independent of APOE genotype.

Age of Onset↗
PubMed2000

Localization, expression and genomic structure of the gene encoding the human serine protease testisin.

Testisin is a recently identified human serine protease expressed by premeiotic testicular germ cells and is a candidate tumor suppressor for testicular cancer. Here, we report the characterization of the gene encoding testisin, designated PRSS21, and its localization on the short arm of human chromosome 16 (16p13.3) between the microsatellite marker D16S246 and the radiation hybrid breakpoint CY23HA. We have further refined the localization to cosmid 406D6 in this interval and have established that the gene is approximately 4. 5 kb in length, and contains six exons and five intervening introns. The structure of PRSS21 is very similar to the human prostasin gene (PRSS8) which maps nearby on 16p11.2, suggesting that these genes may have evolved through gene duplication. Sequence analysis showed that the two known isoforms of testisin are generated by alternative pre-mRNA splicing. A major transcription initiation site was identified 97 nucleotides upstream of the testisin translation start and conforms to a consensus initiator element. The region surrounding the transcription initiation site lacks a TATA consensus sequence, but contains a CCAAT sequence and includes a CpG island. The 5'-flanking region contains several consensus response elements including Sp1, AP1 and several testis-specific elements. Analysis of testisin gene expression in tumor cell lines shows that testisin is not expressed in testicular tumor cells but is aberrantly expressed in some tumor cell lines of non-testis origin. These data provide the basis for identifying potential genetic alterations of PRSS21 that may underlie both testicular abnormalities and tumorigenesis.

Alternative Splicing↗
PubMed2000

Segmental expression of Hoxb2 in r4 requires two separate sites that integrate cooperative interactions between Prep1, Pbx and Hox proteins.

Direct auto- and cross-regulatory interactions between Hox genes serve to establish and maintain segmentally restricted patterns in the developing hindbrain. Rhombomere r4-specific expression of both Hoxb1 and Hoxb2 depends upon bipartite cis Hox response elements for the group 1 paralogous proteins, Hoxal and Hoxbl. The DNA-binding ability and selectivity of these proteins depend upon the formation of specific heterodimeric complexes with members of the PBC homeodomain protein family (Pbx genes). The r4 enhancers from Hoxb1 and Hoxb2 have the same activity, but differ with respect to the number and organisation of bipartite Pbx/Hox (PH) sites required, suggesting the intervention of other components/sequences. We report here that another family of homeodomain proteins (TALE, Three-Amino acids-Loop-Extension: Prep1, Meis, HTH), capable of dimerizing with Pbx/EXD, is involved in the mechanisms of r4-restricted expression. We show that: (1) the r4-specific Hoxb1 and Hoxb2 enhancers are complex elements containing separate PH and Prep/Meis (PM) sites; (2) the PM site of the Hoxb2, but not Hoxb1, enhancer is essential in vivo for r4 expression and also influences other sites of expression; (3) both PM and PH sites are required for in vitro binding of Prepl-Pbx and formation and binding of a ternary Hoxbl-Pbxla (or 1b)-Prepl complex. (4) A similar ternary association forms in nuclear extracts from embryonal P19 cells, but only upon retinoic acid induction. This requires synthesis of Hoxbl and also contains Pbx with either Prepl or Meisl. Together these findings highlight the fact that PM sites are found in close proximity to bipartite PH motifs in several Hox responsive elements shown to be important in vivo and that such sites play an essential role in potentiating regulatory activity in combination with the PH motifs.

Animals↗
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

Spatial and temporal trends of contaminants in Canadian Arctic freshwater and terrestrial ecosystems: a review.

The state of knowledge of contaminants in Canadian Arctic biota of the freshwater and terrestrial ecosystems has advanced enormously since the publication of the first major reviews by Lockhart et al. and Thomas et al. in The Science of the Total Environment in 1992. The most significant gains are new knowledge of spatial trends of organochlorines and heavy metal contaminants in terrestrial animals, such as caribou and mink, and in waterfowl, where no information was previously available. Spatial trends in freshwater fish have been broadened, especially in the Yukon, where contaminant measurements of, for example, organochlorines were previously non-existent. A review of contaminants data for fish from the Northwest Territories, Yukon and northern Quebec showed mercury as the one contaminant which consistently exceeds guideline limits for subsistence consumption or commercial sale. Lake trout and northern pike in the Canadian Shield lakes of the Northwest Territories and northern Quebec generally had the most elevated levels. Levels of other heavy metals were generally not elevated in fish. Toxaphene was the major organochlorine contaminant in all fish analyzed. The concentrations of organochlorine contaminants in fish appear to be a function not only of trophic level but of other aspects of the lake ecosystem. Among Arctic terrestrial mammals, PCBs and cadmium were the most prominent contaminants in the species analyzed. Relatively high levels (10-60 micrograms g-1) of cadmium were observed in kidney and liver of caribou from the Yukon, the Northwest Territories and northern Quebec, with concentrations in western herds being higher than in those from the east. For the organochlorine contaminants, a west to east increase in zigma PCBs, HCB and zigma HCH was found in caribou, probably as a result of the predominant west to east/north-east atmospheric circulation pattern which delivers these contaminants from industrialized regions of central and eastern North America to the Arctic via long-range atmospheric transport. Radiocesium contamination of lichens and caribou has continued to decrease. Significant contamination by PCBs and lead of soils and vascular plants was observed in the immediate vicinity and within a 20-km radius of DEW line sites in the Canadian Arctic. There was also evidence for transfer of PCBs from plants to lemmings. There was no evidence, however, that large mammals such as caribou living in the general area of the DEW line sites had elevated levels of PCBs. There is very limited temporal trend information for most contaminants in biota of Arctic terrestrial and freshwater environments.

Animals↗
PubMed1999

Morphological assessment of the soft palate in habitual snoring using image analysis.

OBJECTIVES: Define differences in palatal and uvular dimensions between habitual snorers and healthy nonsnoring control subjects. Document the changes in palatal configuration after different types of palatoplasty. STUDY DESIGN: A prospective controlled clinical study was performed analyzing video recordings of the soft palate and oropharynx of 251 subjects (121 habitual snorers, 79 patients after laser-assisted uvulopalatoplasty ([LAUP], and 51 healthy volunteers). METHODS: The recordings were captured using a rigid endoscope with a reference measure applied to the soft palate and a mark at the junction of the soft and hard palate. Four parameters were studied in the captured pictures after correction for the distortion deformity in fiberoptic endoscopic images: 1) length of soft palate, 2) length of uvula, 3) width of uvula, and 4) distance between posterior pillars. RESULTS: Analysis showed that habitual snorers, compared with healthy volunteers have significantly increased soft palate length (P = .00001), increased uvula length (P = .0002) and width (P = .00001), and narrowed oropharyngeal isthmus (distance between the posterior pillars) (P = .04). In patients studied after LAUP, the length of the soft palate is significantly shorter (P = .00001) than in the preoperative cohort, and the oropharyngeal isthmus is significantly narrower (P = .00001). Moreover, this latter distance is significantly narrower (P = .00001) when compared with healthy volunteers. CONCLUSIONS: Habitual snorers have a long soft palate, a long wide uvula, and a narrowed oropharyngeal isthmus. LAUP shortens and tightens the elongated palate and causes a further reduction in the space between the posterior pillars.

Adult↗
PubMed1998

A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome).

Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy. Linkage to markers on chromosome 4p was confirmed in five families. On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb. Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype. WFS1 appears to function in survival of islet beta-cells and neurons.

Adult↗
PubMed1998

Two pine endo-beta-1,4-glucanases are associated with rapidly growing reproductive structures.

Two cDNA clones encoding endo-beta-1,4-glucanases (EGases) were isolated from a radiata pine (Pinus radiata) cDNA library prepared from immature female strobili. The cDNAs PrCel1 (inus adiata cellulase ) and PrCel2 encode proteins 509 and 515 amino acids in length, respectively, including putative signal peptides. Both proteins contain domains conserved in plant and bacterial EGases. The proteins PRCEL1 and PRCEL2 showed strong similarity to each other (76% amino acid identity), and higher similarity to TPP18 (73 and 67%, respectively), an EGase cloned from tomato (Lycopersicon esculentum) pistils, than to any other reported EGases. Northern-blot analyses indicated that both genes displayed a similar pattern of expression. The only significant difference was in the level of expression. In situ hybridizations were used to demonstrate that, within differentiating pine reproductive structures, PrCel1 expression was greatest in microsporangia in pollen strobili and near the developing ovule in the seed strobili. Expression was also found in vegetative tissues, especially in regions experiencing cell elongation, such as the elongating region of root tips. Both proteins have an ability to degrade carboxymethylcellulose in vitro. Genomic-blot analysis indicated the presence of a family of EGase genes in the radiata pine genome, and that PrCel1 and PrCel2 are transcribed from distinct one-copy genes.

Bacterial Proteins↗
PubMed1998

Eucalypt MADS-box genes expressed in developing flowers.

Three MADS-box genes were identified from a cDNA library derived from young flowers of Eucalyptus grandis W. Hill ex Maiden. The three egm genes are single-copy genes and are expressed almost exclusively in flowers. The egm1 and egm3 genes shared strongest homology with other plant MADS-box genes, which mediate between the floral meristem and the organ-identity genes. The egm3 gene was also expressed strongly in the receptacle or floral tube, which surrounds the carpels in the eucalypt flower and bears the sepals, petals, and numerous stamens. There appeared to be a group of genes in eucalypts with strong homology with the 3' region of the egm1 gene. The egm2 gene was expressed in eucalypt petals and stamens and was most homologous to MADS-box genes, which belong to the globosa group of genes, which regulate organogenesis of the second and third floral whorls. The possible role of these three genes in eucalypt floral development is discussed.

Amino Acid Sequence↗
PubMed1998

Genetic interactions between Hoxa1 and Hoxb1 reveal new roles in regulation of early hindbrain patterning.

In the developing vertebrate hindbrain Hoxa1 and Hoxb1 play important roles in patterning segmental units (rhombomeres). In this study, genetic analysis of double mutants demonstrates that both Hoxa1 and Hoxb1 participate in the establishment and maintenance of Hoxb1 expression in rhombomere 4 through auto- and para-regulatory interactions. The generation of a targeted mutation in a Hoxb1 3' retinoic acid response element (RARE) shows that it is required for establishing early high levels of Hoxb1 expression in neural ectoderm. Double mutant analysis with this Hoxb1(3'RARE) allele and other targeted loss-of-function alleles from both Hoxa1 and Hoxb1 reveals synergy between these genes. In the absence of both genes, a territory appears in the region of r4, but the earliest r4 marker, the Eph tyrosine kinase receptor EphA2, fails to be activated. This suggests a failure to initiate rather than maintain the specification of r4 identity and defines new roles for both Hoxb1 and Hoxa1 in early patterning events in r4. Our genetic analysis shows that individual members of the vertebrate labial-related genes have multiple roles in different steps governing segmental processes in the developing hindbrain.

Animals↗