Search PubMed⌕ Search

Biomedical subjects

J C Murray

Publications and source records attributed to J C Murray.

At least 55 records · Page 3Linked to original sources
PubMed2000

Antagonistic signals between BMP4 and FGF8 define the expression of Pitx1 and Pitx2 in mouse tooth-forming anlage.

Members of the Pitx/RIEG family of homeodomain-containing transcription factors have been implicated in vertebrate organogenesis. In this study, we examined the expression and regulation of Pitx1 and Pitx2 during mouse tooth development. Pitx1 expression is detected in early development in a widespread pattern, in both epithelium and mesenchyme, covering the tooth-forming region in the mandible, and is then maintained in the dental epithelium from the bud stage to the late bell stage. Pitx2 expression, on the other hand, is restricted to the dental epithelium throughout odontogenesis. Interestingly, from E9.5 to E10.5, the expression domains of Pitx1 and Pitx2, in the developing mandible, overlap with that of Fgf8 but are exclusive to the zone of Bmp4 expression. Bead implantation experiments demonstrate that ectopic expression of Fgf8 can induce/maintain the expression of both Pitx1 and Pitx2 at E9.5. In contrast, Bmp4-expressing tissues and BMP4-soaked beads were able to repress Pitx1 expression in mandibular mesenchyme and Pitx2 expression in the presumptive dental epithelium, respectively. However, the effects of FGF8 and BMP4 are transient. It thus appears that the early expression patterns of Pitx1 and Pitx2 in the developing mandible are regulated by the antagonistic effects of FGF8 and BMP4 such that the Pitx1 and Pitx2 expression patterns are defined. These results indicate that the epithelial-derived signaling molecules are responsible not only for restricting specific gene expression in the dental mesenchyme, but also for defining gene expression in the dental epithelium.

Animals↗
PubMed2000

Isolation and characterization of a novel human paired-like homeodomain-containing transcription factor gene, VSX1, expressed in ocular tissues.

Homeodomain transcription factors control cell fates during the development of all animals. The paired-like subfamily of homeodomain proteins has been particularly implicated in ocular development in different species. In this paper we report the cDNA sequence, genomic structure, localization, and expression data of a novel paired-like homeobox-containing gene, VSX1, isolated from a human embryonic craniofacial cDNA library using the degenerate-PCR approach. The composed VSX1 cDNA sequence of 1433 bp was predicted to encode a protein of 365 amino acid residues. Maximal homology at the protein level was identified with the paired-like homeoproteins of the CVC-domain family: 92-97% identity was seen in the homeodomain region with 55% overall identity to zebrafish and goldfish Vsx1 and 35% overall identity to goldfish Vsx2 and murine Chx10. The gene was found to consist of five exons that are distributed over 6.2 kb of genomic sequence. VSX1 was localized to the 20p11-q11 region, which is homologous with the distal part of mouse chromosome 2. Expression of VSX1 was detected in embryonic craniofacial and adult ocular tissues. Several ocular phenotypes have been mapped to the VSX1 region in both human and mouse genomes, and its candidacy for these disorders is discussed.

Animals↗
PubMed2000

The Pitx2 protein in mouse development.

The Rieger syndrome, an autosomal dominant disorder involving ocular, dental, and umbilical defects is caused by mutations in PITX2, a Bicoid-type homeobox protein. Mouse Pitx2 mRNA is expressed in eye, tooth and umbilicus consistent with the human Riegers phenotype. Moreover, Pitx2 is involved in the Nodal/Sonic hedgehog pathway that determines left/right polarity. In this report we demonstrate a 32-kDa polypeptide on Western blots of nuclear extracts from a rat pituitary cell line, using a Pitx2 specific antibody (designated P2R10). We describe also for the first time expression of the Pitx2 protein in mouse. Pitx2 protein immunostaining was detectable during the development of the eye, tooth, umbilicus, and also in the pituitary, heart, gut, and limb. We demonstrate for the first time directly that Pitx2 is asymmetrically expressed in early heart, gut, and lung development.

Abnormalities, Multiple↗
PubMed2000

Localization of dominantly inherited isolated triphalangeal thumb to chromosomal region 7q36.

Triphalangeal thumb is an autosomal dominantly inherited form of abnormal preaxial skeletal development. In most families, however, the triphalangeal thumb phenotype coexists with a spectrum of limb deformities, including polydactyly and syndactyly. We describe two Iowa kindreds with triphalangeal thumb. In one family, with nine affected members, triphalangeal thumb was the only manifestation of limb deformity. We performed linkage analysis on both pedigrees, demonstrating a maximum LOD score of 6.23 with marker D7S559 on chromosome 7q36. This corresponds to a previous study of a candidate region of 450 kb in which data from several families with preaxial polydactyly were employed. Further analysis of the unique family with isolated triphalangeal thumb in the current study may demonstrate allelic variability of the gene involved in these disorders.

Chromosome Mapping↗
PubMed2000

Immunohistochemical analysis of endothelial-monocyte-activating polypeptide-II expression in vivo.

Endothelial-monocyte activating polypeptide (EMAP)-II is a novel molecule with cytokine-like pro-inflammatory properties, inducing procoagulant activity on the surface of endothelial cells and monocyte/macrophages in vitro, as well as up-regulating E- and P-selectin expression. EMAP-II is chemotactic for monocytes/macrophages and neutrophils, and stimulates myeloperoxidase release from neutrophils. Injection of EMAP-II into the mouse footpad induces an acute inflammatory response, although some regression occurs in response to direct injection of EMAP-II into murine tumors. Very little is known about the expression of EMAP-II in normal tissues of mice or humans, or about its function in vivo. We developed polyclonal antibodies against EMAP-II using recombinant protein produced in Escherichia coli, and used these antibodies to carry out an immunohistochemical study of the occurrence and distribution of EMAP-II in human tissues. The distribution of EMAP-II protein is relatively restricted, occurring primarily in endocrine organs, in cells of neuroendocrine origin, but also in tissues with high turnover. EMAP-II is strongly expressed in secretory epithelial cells of the thyroid, pancreas, adrenal and salivary glands, among others, as well as in neurons and subsets of monocytes/macrophages. It is also found in the epithelium of the small and large intestines. We conclude that EMAP-II expression is usually, but not always, associated with tissues that display high turnover and high levels of protein synthesis.

Cardiovascular System↗
PubMed2000

Modern approaches to photoprotection.

UV light reacts with skin to produce undesirable changes, including photoaging and skin cancer. Sunscreen strategies are useful for protection against UV-B and short-wave UV-A, but complete protection against long-wave UV-A has not been achieved. Because UV-A is especially efficient at generating reactive oxygen species, it is being recognized increasingly as an important cause of photoaging and skin cancer.

Antioxidants↗
PubMed2000

Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease.

Camurati-Engelmann disease (CED, MIM 131300) is an autosomal dominant, progressive diaphyseal dysplasia characterized by hyperosteosis and sclerosis of the diaphyses of long bones. We recently assigned the CED locus to an interval between D19S422 and D19S606 at chromosome 19q13.1-q13.3, which two other groups confirmed. As the human transforming growth factor-1 gene (TGFB1) is located within this interval, we considered it a candidate gene for CED.

Base Sequence↗
PubMed2000

Platelet-derived endothelial cell growth factor expression and angiogenesis in cervical intraepithelial neoplasia and squamous cell carcinoma of the cervix.

Growth and metastatic spread of invasive carcinoma depends on angiogenesis, the formation of new blood vessels. Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic growth factor for a number of solid tumors, including lung, bladder, colorectal, and renal cell cancer. Cervical intraepithelial neoplasia (CIN) is the precursor to squamous cell cervical carcinoma (SCC). Mean vessel density (MVD) increases from normal cervical tissue, through low- and high-grade CIN to SCC. We evaluated PD-ECGF immunoreactivity and correlated its expression with MVD in normal, premalignant, and malignant cervical tissue. PD-ECGF expression was assessed visually within the epithelial tissues and scored on the extent and intensity of staining. MVD was calculated by counting the number of vessels positive for von Willebrand factor per unit area subtending normal or CIN epithelium or within tumor hotspots for SCC. Cytoplasmic and/or nuclear PD-ECGF immunoreactivity was seen in normal epithelium. PD-ECGF expression significantly increased with histologic grade from normal, through low- and high-grade CIN, to SCC (P < .02). A progressive significant increase in the microvessel density was also seen, ranging from a mean of 28 vessels for normal tissue to 57 for SCC (P < .0005). No correlation was found between PD-ECGF expression and MVD (P = .45). We conclude that PD-ECGF expression and MVD increase as the cervix transforms from a normal to a malignant phenotype. PD-ECGF is thymidine phosphorylase, a key enzyme in the activation of fluoropyrimidines, including 5-fluorouracil. Evaluation of PD-ECGF thymidine phosphorylase expression may be important in designing future chemotherapeutic trials in cervical cancer.

Carcinoma, Squamous Cell↗
PubMed2000

A preliminary gene map for the Van der Woude syndrome critical region derived from 900 kb of genomic sequence at 1q32-q41.

Van der Woude syndrome (VWS) is a common form of syndromic cleft lip and palate and accounts for approximately 2% of all cleft lip and palate cases. Distinguishing characteristics include cleft lip with or without cleft palate, isolated cleft palate, bilateral lip pits, hypodontia, normal intelligence, and an autosomal-dominant mode of transmission with a high degree of penetrance. Previously, the VWS locus was mapped to a 1.6-cM region in 1q32-q41 between D1S491 and D1S205, and a 4.4-Mb contig of YAC clones of this region was constructed. In the current investigation, gene-based and anonymous STSs were developed from the existing physical map and were then used to construct a contig of sequence-ready bacterial clones across the entire VWS critical region. All STSs and BAC clones were shared with the Sanger Centre, which developed a contig of PAC clones over the same region. A subset of 11 clones from both contigs was selected for high-throughput sequence analysis across the approximately 1.1-Mb region; all but two of these clones have been sequenced completely. Over 900 kb of genomic sequence, including the 350-kb VWS critical region, were analyzed and revealed novel polymorphisms, including an 8-kb deletion/insertion, and revealed 4 known genes, 11 novel genes, 9 putative genes, and 3 psuedogenes. The positional candidates LAMB3, G0S2, HIRF6, and HSD11 were excluded as the VWS gene by mutation analysis. A preliminary gene map for the VWS critical region is as follows: [see text] 41-TEL. The data provided here will help lead to the identification of the VWS gene, and this study provides a model for how laboratories that have a regional interest in the human genome can contribute to the sequencing efforts of the entire human genome.

Animals↗
PubMed1999

The human BARX2 gene: genomic structure, chromosomal localization, and single nucleotide polymorphisms.

The BARX genes 1 and 2 are Bar class homeobox genes expressed in craniofacial structures during development. In this report, we present the genomic structure, chromosomal localization, and polymorphic markers in BARX2. The gene has four exons, ranging in size from 85 to 1099 bp. BARX2 is localized on human chromosome 11q25, as determined by radiation hybrid mapping. In the mouse, Barx2 is coexpressed with Pitx2 in several tissues. Based on the coexpression, BARX2 was assumed to be a candidate gene for those cases of Rieger syndrome that cannot be associated with mutations of PITX2. Mutations in PITX2 cause some cases of Rieger syndrome, an autosomal dominant disorder affecting eyes, teeth, and umbilicus. DNA from Rieger patients was subjected to single-strand conformation polymorphism screening of the BARX2 coding region. Three single nucleotide polymorphisms were found in a normal population, although no etiologic mutations were detectable in over 100 cases of Rieger syndrome or in individuals with related ocular disorders.

Alleles↗
PubMed1999

Transforming growth factor-alpha (TGFA): genomic structure, boundary sequences, and mutation analysis in nonsyndromic cleft lip/palate and cleft palate only.

Transforming growth factor-alpha (TGFA) has been proposed as a candidate gene in the etiology of nonsyndromic cleft lip with or without cleft palate (NS-CL/P) and of nonsyndromic cleft palate only (NS-CPO). Biologic support for a role of TGFA arises from its presence at high levels in the epithelial tissue of the medial edge of the palatal shelves at the time of shelf fusion in mice. Genetic support for the role of TGFA in clefting comes from the reported association of TGFA alleles with human NS-CPO and NS-CL/P. In this study we report the sequence and structure of human genomic TGFA and the search for causal TGFA mutations in 250 individuals with NS-CL/P or NS-CPO by conformational analysis of the coding sequence, splice junctions, and a portion of the 3' untranslated region strongly homologous between human and mouse. We confirm that human TGFA is composed of six exons and here report several new sequence substitutions and their frequencies. Five variants in conserved segments may represent rare causes for clefting in humans and provide support for the role of TGFA in facial morphogenesis.

Animals↗
PubMed1999

Microdeletions at chromosome bands 1q32-q41 as a cause of Van der Woude syndrome.

Van der Woude syndrome (VWS) is an autosomal dominant disorder comprising cleft lip and/or cleft palate and lip pits. We reported previously a family whose underlying mutation is a 500-800 kb deletion localized to chromosome bands 1q32-q41 [Sander et al., 1994: Hum Mol Genet 3:576-578]. Along with cleft lip/palate and lip pits, affected relatives exhibit developmental delays, suggesting that the function of a gene nearby may also be disrupted. To further localize the VWS gene we searched for other deletions that cause VWS. An allele loss assay was performed using a novel highly polymorphic marker, D1S3753. From a panel of 37 unrelated individuals, we detected an allele loss in one family, indicating the presence of a deletion. In this family, the phenotype in three generations of affected individuals was confined to the cardinal signs of VWS. Surprisingly, mapping of the new deletion showed that it extended 0.2-1 Mb beyond the proximal breakpoint for the deletion described previously. No deletions were detected in seven cases of popliteal pterygia syndrome, 76 cases of mixed syndromic forms of cleft lip and palate, and 178 cases of nonsyndromic cleft lip and palate. These observations suggest that genetic searches for microdeletions should be routine in screening patients for causes of VWS and may facilitate the positional cloning efforts of the VWS gene and of a nearby gene or genes that may be involved in brain development.

Anodontia↗
PubMed1999

Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: a population-based case-control study in Denmark, 1991-1994.

Studies in the United States have indicated that maternal first trimester smoking and infant transforming growth factor alpha (TGFA) locus mutations are associated with non-syndromic cleft lip and/or palate (CLP) and that a synergistic effect of these two risk factors occurs. Based on a Danish case-control study of CLP, the authors studied the effects of smoking and TGFA alleles in an ethnically homogeneous setting. Interview information was obtained for mothers of 302 CLP cases (96% of eligible) and for 567 mothers of nonmalformed children (94% of eligible). Multivariate logistic regression analyses revealed that smoking was associated with a moderately increased risk of cleft lip +/- cleft palate (CL(P)) (odds ratio = 1.40, 95% confidence interval 0.99-2.00). No association between smoking and isolated cleft palate (CP) was observed. TGFA genotype was not associated with either CL(P) or CP, and no synergistic effect with smoking was observed. The "rare" TGFA allele occurred in 25% of both cases and controls compared with an average of 14% in other white control groups. Furthermore, the frequency of CLP in Scandinavia is among the highest in the world. Hence, it is possible that the previously reported association between TGFA and CLP to some degree can be attributable to confounding by ethnicity.

Adult↗
PubMed1999

Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts.

Previous studies suggest that the relationship between genes and nonsyndromic cleft lip +/- cleft palate (CLP) or cleft palate only (CP) may be modified by the environment. Using data from a population-based case-control study, we examined allelic variants for three genes, i.e., transforming growth factor alpha (TGFA), transforming growth factor beta 3 (TGFB3), and Msh (Drosophila) homeobox homolog 1 (MSX1), and their interactions with two exposures during pregnancy (maternal cigarette smoking and alcohol consumption) as risk factors for CLP and CP. For each cleft phenotype, risk estimates associated with most allelic variants tended to be near unity. Risk estimates for maternal smoking (> or = 10 cigarettes/day) were significantly elevated for CP and were most elevated among infants with allelic variants at the TGFB3 or MSX1 sites. By comparison, risk estimates for maternal alcohol consumption (> or = 4 drinks/month) were significantly elevated for CLP and were most elevated among infants with allelic variants at the MSX1 site. Our results suggest that development of CLP and CP may be influenced independently by maternal exposures but more significantly by interaction of such exposures and specific allelic variants.

Alcohol Drinking↗
PubMed1999

Analysis of select folate pathway genes, PAX3, and human T in a Midwestern neural tube defect population.

Neural tube defects (NTDs) are a common birth defect, seen in approximately 1/1,000 births in the United States. NTDs are considered a complex trait where several genes, interacting with environmental factors, create the phenotype. Using a Midwestern NTD population consisting of probands, parents, and siblings from Iowa, Minnesota, and Nebraska, we analyzed a range of candidate genes, including 5,10-methylenetetrahydrofolate reductase (MTHFR), folate receptors-alpha (FOLR1; hereafter abbreviated "FR-alpha") and -beta (FOLR2; hereafter, "FR-beta"), methionine synthase (hereinafter, "MS"), T, the human homolog of the murine Brachyury gene, and the paired-box homeotic gene 3 (PAX3), for association with NTDs. We were unable to demonstrate an association using a previously described Ala-->Val mutation in MTHFR and the majority of our NTD populations. However, we discovered a silent polymorphism in exon 6 of MTHFR which conserved a serine residue and which showed significant association with NTDs in our Iowa population. Analysis of exon 7 of MTHFR then demonstrated an Ala-->Glu mutation which was significantly associated with our Iowa NTD population; however, we could not replicate this result either in a combined Minnesota/ Nebraska or in a California NTD population. Using polymorphic markers for MS, FR-beta, T, and PAX3, we were unable to demonstrate linkage disequilibrium with our NTD populations. A mutation search of FR-alpha revealed one proband with a de novo silent mutation of the stop codon. This work provides a new panel of genetic variants for studies of folate metabolism and supports, in some NTD populations, an association between MTHFR and NTDs.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1999

Changes in microvessel endothelial cell gene expression in an in vitro human breast tumour endothelial cell model.

Selective targeting of tumour-endothelium has been proposed as a means of therapy. The successful exploitation of this approach will rely on the identification of suitable targets expressed specifically on the tumour-associated endothelium. In an attempt to identify novel tumour-endothelium associated targets we have used differential mRNA display to identify genes up-regulated in an in vitro breast tumour-endothelial cell culture model. Confluent monolayers of human mammary microvessel endothelial cells (HuMMEC) were incubated for 5 days with MDA-MB-231 breast adenocarcinoma cell-conditioned medium (TCM). mRNAs isolated from TCM-treated and control cells were amplified using 104 combinations of four 3(') anchored T(12)VN primers and 26 'random' 10mers by RT-PCR and the products examined on DNA sequencing gels. Seventy-four sequences were cloned and the differential expression of five genes was confirmed using dot-blots. These were identified as procollagen type-IV, Tie-2/Tek receptor tyrosine kinase, NADH dehydrogenase subunit-6, and ferritin heavy-chain, which were up-regulated, and insulin-like growth factor binding protein-5, which was down-regulated. Increased endothelial expression of basement membrane proteins and tyrosine kinase receptors is known to occur during angiogenesis. Our data support the use of this model for further in vitro investigation of tumour angiogenesis.

Journal Article↗