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PubMed2001

Hedgehog-dependent oligodendrocyte lineage specification in the telencephalon.

In the caudal neural tube, oligodendrocyte progenitors (OLPs) originate in the ventral neuroepithelium under the influence of Sonic hedgehog (SHH), then migrate throughout the spinal cord and brainstem before differentiating into myelin-forming cells. We present evidence that oligodendrogenesis in the anterior neural tube follows a similar pattern. We show that OLPs in the embryonic mouse forebrain express platelet-derived growth factor alpha-receptors (PDGFRA), as they do in more caudal regions. They first appear within a region of anterior hypothalamic neuroepithelium that co-expresses mRNA encoding SHH, its receptor PTC1 (PTCH) and the transcription factors OLIG1, OLIG2 and SOX10. Pdgfra-positive progenitors later spread through the forebrain into areas where Shh is not expressed, including the cerebral cortex. Cyclopamine inhibited OLP development in cultures of mouse basal forebrain, suggesting that hedgehog (HH) signalling is obligatory for oligodendrogenesis in the ventral telencephalon. Moreover, Pdgfra-positive progenitors did not appear on schedule in the ventral forebrains of Nkx2.1 null mice, which lack the telencephalic domain of Shh expression. However, OLPs did develop in cultures of Nkx2.1(-/-) basal forebrain and this was blocked by cyclopamine. OLPs also developed in neocortical cultures, even though Shh transcripts could not be detected in the embryonic cortex. Here, too, the appearance of OLPs was suppressed by cyclopamine. In keeping with these findings, we detected mRNA encoding SHH and Indian hedgehog (IHH) in both Nkx2.1(-/-) basal forebrain cultures and neocortical cultures. Overall, the data are consistent with the idea that OLPs in the telencephalon, possibly even some of those in the cortex, develop under the influence of SHH in the ventral forebrain.

Animals↗
PubMed2002

Specification of an anterior neuroectoderm patterning by Frizzled8a-mediated Wnt8b signalling during late gastrulation in zebrafish.

Wnts have been shown to provide a posteriorizing signal that has to be repressed in the anterior neuroectoderm for normal anteroposterior (AP) patterning. We have previously identified a zebrafish frizzled8a (fz8a) gene expressed in the presumptive anterior neuroectoderm as well as prechordal plate at the late gastrula stage. We have investigated the role of Fz8a-mediated Wnt8b signalling in anterior brain patterning in zebrafish. We show that in zebrafish embryos: (1) Wnt signalling has at least two different stage-specific posteriorizing activities in the anterior neuroectoderm, one before mid-gastrulation and the other at late gastrulation; (2) Fz8a plays an important role in mediating anterior brain patterning; (3) Wnt8b and Fz8a can functionally interact to transmit posteriorizing signals that determine the fate of the posterior diencephalon and midbrain in late gastrula embryos; and (4) Wnt8b can suppress fz8a expression in the anterior neuroectoderm and potentially affect the level and/or range of Wnt signalling. In conclusion, we suggest that a gradient of Fz8a-mediated Wnt8b signalling may play crucial role in patterning the posterior diencephalon and midbrain regions in the late gastrula.

Animals↗
PubMed2005

Loss of the modifiers of variegation Su(var)3-7 or HP1 impacts male X polytene chromosome morphology and dosage compensation.

Loss of Su(var)3-7 or HP1 suppresses the genomic silencing of position-effect variegation, whereas over-expression enhances it. In addition, loss of Su(var)3-7 results in preferential male lethality. In polytene chromosomes deprived of Su(var)3-7, we observe a specific bloating of the male X chromosome, leading to shortening of the chromosome and to blurring of its banding pattern. In addition, the chromocenter, where heterochromatin from all polytene chromosomes fuses, appears decondensed. The same chromosomal phenotypes are observed as a result of loss of HP1. Mutations of Su(var)3-7 or of Su(var)2-5, the gene encoding HP1, also cause developmental defects, including a spectacular increase in size of the prothoracic gland and its polytene chromosomes. Thus, although structurally very different, the two proteins cooperate closely in chromosome organization and development. Finally, bloating of the male X chromosome in the Su(var)3-7 mutant depends on the presence of a functional dosage compensation complex on this chromosome. This observation reveals a new and intriguing genetic interaction between epigenetic silencing and compensation of dose.

Animals↗
PubMed1997

Epitopes of adhesion-perturbing monoclonal antibodies map within a predicted alpha-helical domain of the integrin beta 1 subunit.

Several recent studies have demonstrated the involvement of various domains of the beta 1 integrin subunit in ligand binding. Thus, specific amino acids have been shown to be important in divalent cation binding, and others have been implicated by peptide crosslinking to play an intimate role in integrin-ligand interactions. Added to these data are previous observations that a group of adhesion-blocking anti-chicken beta 1 antibodies mapped within the first 160 amino acid residues of the subunit. These observations suggested that this region plays a critical role in integrin ligand recognition. In order to further define the domain in which the epitopes for these antibodies are clustered, a series of mouse/chicken chimeric beta 1 constructs were examined for their reactivity with each of these antibodies. Most of the antibodies recognize a region between residues 124 to 160 of the chicken beta 1 subunit. Computer modeling predicted a possible amphipathic alpha-helical configuration for the region between residues 141 to 160. Consistent with this prediction, circular dichroism and NMR analysis revealed a tendency for a synthetic peptide containing these residues to form an alpha-helix. The significance of this structural characteristic was demonstrated by a mutation at residue 149 that disrupted the alpha-helix formation and resulted in a loss of the ability to form heterodimers with alpha subunits, localize to focal contacts, or be transported to the cell surface. The direct involvement of residues 141 to 160 in ligand binding was supported by the ability of a peptide with this sequence to elute integrins from a fibronectin affinity column. Thus, our data suggest that residues 141 to 160 of the integrin beta 1 subunit, when arranged in an alpha-helix configuration, participate in ligand binding.

3T3 Cells↗
PubMed2004

[Identification of muscle-type carnitine palmitoyltransferase I and characterization of its gene structure].

To characterize energy metabolism in brown adipose tissue (BAT), differential screening of a cDNA library of rat BAT with a cDNA probe of rat white adipose tissue was carried out. We isolated one novel cDNA clone encoding a protein of 88.2 kDa consisting of 772 amino acids. The deduced amino acid sequence showed the highest homology (62.6%) with that of rat liver carnitine palmitoyltransferase I (CPTI). The transcript corresponding to this cDNA was abundantly expressed not only in BAT but also in the heart and skeletal muscle. CPTI is a protein necessary for the beta-oxidation of long-chain fatty acids in mammalian mitochondria, and it has been suggested that at least two isoforms, the liver type and muscle (M-CPTI) type, exist. Based on these observations, we concluded that the novel cDNA clone isolated from rat BAT encodes M-CPTI. Isolation and characterization of a genomic DNA clone revealed that the gene for human M-CPTI consists of two 5'-noncoding exons, 18 coding exons, and one 3'-noncoding exon spanning approximately 10 kbp, and a gene encoding choline/ethanolamine kinase-beta (CK/EK-beta) was located about 300 bp upstream from the M-CPTI gene with the same strand direction. Furthermore, we found atypical transcripts containing exons of both CK/EK-beta and M-CPTI genes in humans and rodents. The physiologic role(s) of these transcripts is still unknown. However, it is interesting that such transcripts are produced from two tightly arranged and functionally unrelated genes in mammalian tissues.

Adipose Tissue, Brown↗
PubMed2005

Human galectin-2: expression profiling by RT-PCR/immunohistochemistry and its introduction as a histochemical tool for ligand localization.

Sugar-encoded information of glyco-conjugates is translated into cellular responses by endogenous lectins. Galectins stand out against other lectin families due to their wide range of functions including cell adhesion, tissue invasion or growth regulation exerted at extracellular, membrane, cytoplasmic and nuclear sites. This remarkable versatility warrants close scrutiny of their emerging network, in this study with focus on homodimeric human galectin-2. We first detected presence of specific mRNA in various tissue types by processing post mortem and surgical specimens by RT-PCR protocols. Overlap of gene expression was noted with proto-type galectins-1 and -7 and also family members from the other two subgroups. To monitor expression on the level of protein a polyclonal anti-galectin-2 antibody was raised. Immunopositivity was semi-quantitatively assessed in sections of 209 human samples establishing an array both of normal tissues and samples with inflammation or benign/malignant growth. In general, positivity was predominantly epithelial without restriction of staining to certain tissue types, as fittingly indicated by our RT-PCR analysis. Staining was not limited to the cytoplasm but also included nuclear sites. To examine the suitability of the labeled lectin as a histochemical probe we biotinylated galectin-2 under activity-preserving conditions and introduced it to tissue profiling. Specific cytoplasmic staining proved the validity of the concept. Our results encourage systematic histopathologic studies by immuno- and lectin histochemistry, especially by adding galectin-2 as study object to galectin fingerprinting which has already yielded prognostic information on galectins-1, -3, -4 and -8 and hereby contributed to define functional overlap/divergence in this lectin family.

Antibodies↗
PubMed2005

Molecular genetic analysis of the nested Drosophila melanogaster lamin C gene.

Lamins are intermediate filaments that line the inner surface of the nuclear envelope, providing structural support and making contacts with chromatin. There are two types of lamins, A- and B-types, which differ in structure and expression. Drosophila possesses both lamin types, encoded by the LamC (A-type) and lamin Dm0 (B-type) genes. LamC is nested within an intron of the essential gene ttv. We demonstrate that null mutations in LamC are lethal, and expression of a wild-type LamC transgene rescues lethality of LamC but not ttv mutants. Mutations in the human A-type lamin gene lead to diseases called laminopathies. To determine if Drosophila might serve as a useful model to study lamin biology and disease mechanisms, we generated transgenic flies expressing mutant LamC proteins modeled after human disease-causing lamins. These transgenic animals display a nuclear lamin aggregation phenotype remarkably similar to that observed when human mutant A-type lamins are expressed in mammalian cells. LamC aggregates also cause disorganization of lamin Dm0, indicating interdependence of both lamin types for proper lamina assembly. Taken together, these data provide the first detailed genetic analysis of the LamC gene and support using Drosophila as a model to study the role of lamins in disease.

Alleles↗
PubMed2003

Derivation of human embryonic germ cells: an alternative source of pluripotent stem cells.

Based on evidence suggesting similarities to human embryonic stem cells, human embryonic germ (hEG) cells have been advocated as an alternative pluripotent stem cell resource but have so far received limited attention. To redress this imbalance, human fetal gonads were collected for the isolation and culture of primordial germ cells at 7-9 weeks postconception. We provide evidence for the derivation, culture, and differentiation of hEG cells in vitro. This evidence includes the expression of markers characteristic of pluripotent cells, the retention of normal XX or XY karyotypes, and the demonstration of pluripotency, as suggested by the expression of markers indicative of differentiation along the three germ lineages (ectoderm, mesoderm, and endoderm) and an associated loss of pluripotent markers. In assessing this differentiation, however, we also demonstrate a hitherto unacknowledged overlap in gene expression profiles between undifferentiated and differentiated cell types, highlighting the difficulty in ascribing cell lineage by gene expression analyses. Furthermore, we draw attention to the problems inherent in the management of these cells in prolonged culture, chiefly the difficulty in preventing spontaneous differentiation, which hinders the isolation of pure, undifferentiated clonal lines. While these data advocate the pursuit of pluripotent hEG cell studies with relevance to early human embryonic development, culture limitations carry implications for their potential applicability to ambitious cell replacement therapies.

Biomarkers↗
PubMed1995

The hormone-binding domain of Oreochromis aureus estrogen receptor gene: homology comparison with other steroid binding receptors.

Although the estrogen receptor gene of Oreochromis aureus (OaER) shows 85% homology to rainbow trout ER (rtER), the molecular organization of its exons and introns in the hormone-binding E domain is more closely related to the human ER gene. Comparison with other vertebrates yielded reduced homologies of 64-67%, probably due to evolutionary speciation. The E1 and E2 exons of OaER are interspersed by a short intron of 1.3 kb which is flanked by consensus splice sites. This is in sharp contrast to the 11 kb intron separating E1 and E2 exons of rtER which also displayed a rare GC donor junction. Three conserved cys at 83, 112 and 195, which are important for formation of 3-D ligand-binding pocket were found in OaER. However, the 4th conserved cys is replaced by a ser. This substitution which is the result of a single base mutation probably suggests different affinity for estrogen or transactivation of the OaER gene. Two overlapping steroid binding and receptor dimerization domains have been observed. The E domain of OaER and rtER has diversified significantly from that of other non-piscine vertebrates, such that they form a separate subgroup in the UPGMA tree of steroid receptors.

Amino Acid Sequence↗
PubMed2005

A novel Fc gamma R-defined, IgG-containing organelle in placental endothelium.

Placental transfer of IgG from maternal circulation to that of the fetus is crucial for fetal and newborn immunity. This process requires that IgG broach two cellular layers of the placenta. IgG transport across the first layer, the syncytiotrophoblast, is almost certainly mediated by the MHC-related FcR for IgG, FcRn. The second layer, the villus endothelium, was until recently thought to allow IgG movement nonspecifically by constitutive transcytosis in caveolae. However, we recently showed that villus endothelium expressed a separate FcR for IgG, the inhibitory motif-bearing Fc gammaRIIb2 seen most notably on macrophages and as a minor fraction of the Fc gammaRIIb expressed on B cells. Now, by quantitative microscopy, we find Fc gammaRIIb2 to be expressed abundantly in an unidentifiable and likely novel organelle of the villus endothelium, unassociated with caveolae. About half of these Fc gammaRIIb2 organelles contain IgG; the remainder lack IgG. The majority fraction (approximately 80%) of IgG-containing organelles is associated with Fc gammaRIIb. No IgG-containing organelles are associated with caveolin. These findings are compatible with Fc gammaRIIb-mediated transfer of IgG across the villus endothelium, independent of caveolae.

Animals↗
PubMed1999

Sequence polymorphisms in the chemokines Scya1 (TCA-3), Scya2 (monocyte chemoattractant protein (MCP)-1), and Scya12 (MCP-5) are candidates for eae7, a locus controlling susceptibility to monophasic remitting/nonrelapsing experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE), the principal animal model of multiple sclerosis, is genetically controlled. To date, 13 disease-modifying loci have been identified in the mouse by whole genome scanning using an F2 intercross between EAE-susceptible SJL/J and EAE-resistant B10.S/DvTe mice. Two quantitative trait loci (QTL), eae6 and eae7, on chromosome 11 were identified by classical marker-specific linkage analysis and interval mapping. Both QTL were reported to be associated with severity and duration of clinical signs. eae7 was subsequently shown to be a unique locus controlling the development of monophasic remitting/nonrelapsing EAE. In this study, composite interval mapping resolved eae6 into two linked QTL: eae6a at 0-13 cM is associated with disease severity, and eae6b at 19-28 cM associated with the duration of clinical signs. Additionally, composite interval mapping significantly refined the locations of eae6a, eae6b, and eae7, thereby facilitating systematic candidate gene screening by cDNA sequencing of SJL/J and B10.S/DvTe alleles. Sequence polymorphisms were not seen in Lif and IL12 beta, candidate genes for eae6a and eae6b, respectively. Similarly, cDNA sequence polymorphisms in Nos2, Scya3, Scya4, Scya5, Scya6, Scya7, Scya9, Scya10, and Scya11 were excluded as candidates for eae7. However, multiple sequence polymorphisms resulting in significant amino acid substitutions were identified in Scya1 (TCA-3), Scya2 (monocyte chemoattractant protein (MCP)-1), and Scya12 (MCP-5). Given the role of chemokines in EAE, these sequence polymorphisms are promising candidates for eae7, a locus associated with severity of clinical signs and susceptibility to the shorter, less severe monophasic remitting/nonrelapsing form of disease.

Amino Acid Sequence↗
PubMed2000

Pollen competition in a natural population of Cucurbita foetidissima (Cucurbitaceae).

The pollen competition hypothesis predicts that when the number of pollen grains deposited onto stigmas exceeds the number of ovules, selection can operate in the time frame between deposition and fertilization. Moreover, because of the overlap in gene expression between the two phases of the life cycle, selection on microgametophytes may alter the resulting sporophytic generation. The extent to which pollen competition occurs in nature has been unclear, because tests of the predictions of the pollen competition hypothesis have used cultivars and/or artificial growth conditions and hand-pollination techniques. In this study we used a wild species, Cucurbita foetidissima, in its natural habitat (southern New Mexico) to determine the amount and timing of the arrival of pollen onto stigmas, the relationship between pollen deposition and seed number, and the effects of the intensity of pollen competition on progeny vigor. We found that ∼900 pollen grains are necessary for full seed set and that a single visit by a pollinator results in the deposition of 653.0 ± 101.8 pollen grains. About 29% of the flowers receiving a single pollinator visit had 900 or more pollen grains on its stigma. Moreover, within 2 h of anthesis, >4000 pollen grains were deposited onto a typical stigma, indicating that multiple pollinator visits must have occurred. Fruits produced by multiple visits had greater seed numbers (206 vs. 147) than fruits produced by a single visit. Finally, the progeny produced by multiple pollinator visits were more vigorous than those produced by single visits with respect to five measures of vegetative growth (MANCOVA, Wilks' lambda = 0.96, F(6,370) = 2.54, P < 0.02. These data demonstrate that conditions for pollen competition exist in nature and support the prediction that pollen competition enhances offspring vigor.

Journal Article↗
PubMed2002

Unconventional rules of small nuclear RNA transcription and cap modification in trypanosomatids.

This review focuses on the spliced leader (SL) RNA and uridylic acid-rich small nuclear RNAs (U-snRNAs) involved in pre-mRNA processing in trypanosomatid protozoa, with particular emphasis on the mechanism of transcription and cap formation. The SL RNA plays a central role in mRNA biogenesis by providing the unique cap 4 structure to the 5' end of all mRNAs by trans-splicing. The trimethylguanosine capped U-snRNAs, on the other hand, represent an unusual example among eukaryotic snRNAs in that they are transcribed by RNA polymerase III. This implies the existence of a distinctive mechanism for capping enzyme selection by the transcriptional machinery. Furthermore, the transcription units of U-snRNA genes offer yet another example of the variety of choices that have been established during eukaryotic evolution, namely that an upstream tRNA gene or tRNA-like gene provides extragenic promoter elements for a downstream small RNA gene.

Animals↗
PubMed2003

Strategies for the development of safe and effective DNA vaccines for allergy treatment.

During the past ten years, a great number of studies have demonstrated that injection of plasmid DNA coding for certain genes results in the induction of humoral and cellular immune responses against the respective gene product. The features of DNA vaccines enable a broad range of applications, including the induction of protective immunity against viral, bacterial, and parasitic infections, and open up new perspectives for the treatment of cancer. Furthermore, based on their Th1-promoting properties, DNA vaccines also turned out to balance Th2-mediated immune reactions, a quality which renders them a promising alternative for immunotherapy against allergy. Their unique immunological properties offer new possibilities for the development of vaccines, which do not cause anaphylactic side effects, a major drawback of specific immunotherapy (SIT). In this review, we present approaches to avoid the translation of native allergenic determinants, thus preventing release of allergy mediators stimulated by crosslinking of pre-existing or vaccine-induced IgE antibodies on mast cells. Three approaches are described, which fulfill these requirements: (i) cutting the allergen gene into overlapping fragments, which lack any antigenic determinant of the native allergen, but display the original repertoire of T cell epitopes, (ii) using hypoallergenic derivatives or (iii) fusing the allergen with ubiquitin, thus fragmenting the antigen and destroying its native structure. The presented experiments demonstrate that DNA vaccines are suitable to balance an allergic response in a protective as well as a therapeutic experimental design, thus demonstrating their potential for allergy treatment. In addition to conventional plasmid DNA vaccines, aspects and perspectives of replicon-based DNA vaccines will be discussed.

Allergens↗
PubMed2004

[Comparison of changes in left ventricular gene expression profiles from different cardiac hypertrophy models in rats].

To get insights into the principles of gene expression changes during cardiac hypertrophy, three rat cardiac hypertrophy models were prepared, i.e., suprarenal abdominal aortic stenosis (SRS), arterial-vein fistula (AVF) and continuous jugular vein infusion of norepinephrine (NEi). The cardiac function and structure were analyzed by echocardiograph as well as histological examination. Total RNA of left ventricles was extracted and gene expression profiles were analyzed by cDNA microarray. SRS and NEi induced concentric cardiac hypertrophy and AVF induced eccentric hypertrophy in rats, among which NEi caused obvious cardiac fibrosis. The changes of gene expression profiles were compared comprehensively across different pathologic cardiac hypertrophy models. While gene expression profiles of different cardiac hypertrophy models compared with pairs, parts of the genes involved were found overlapped, and mostly the gene expression changed in the same direction between two models, but some of them changed in the opposite directions. Expression levels of 19 genes were found changed across all cardiac hypertrophy models, and genes relatively regulated in a specific model was also found when comparison of all the three models was carried out. Novel clues for further study might derive from the results mentioned above, and some genes might be the marker genes of cardiac hypertrophy or the targets of therapy.

Animals↗
PubMed2005

Quality control for microarray experiments.

OBJECTIVES: In this paper we give an overview of post-hybridization quality control methods for gene expression chips, including methods for the gene/spot level, the hybridization/chip level and the process level. We present quality control methods that can be applied after hybridization and image analysis, i.e. that use data from the chip experiment itself. Wet lab quality control steps, which should be applied before the probe is measured on a chip, are not discussed. This review is aimed towards statisticians and data analysts. METHODS: We give examples of some of the quality control measures available for spotted cDNA and Affymetrix GeneChips, the most common chip types. As quality control measures are technology and design-dependent, we will stress on methods that have the potential to be applied platform-independently. RESULTS: Quality control should identify poor quality chips or hybridizations, as well as faulty measurements for individual genes/spots. Additionally, high throughput laboratories processing several tens or hundreds of microarrays per week have the need for an appropriate process control to be able to identify changes in the production process as early as possible. CONCLUSION: Microarrays have become a standard research tool for biologists and medical researchers. As a consequence, there is a great need for standardized quality control, as false findings due to problem in data quality can lead to a substantial loss of resources.

DNA Probes↗
PubMed1990

Differential expression of the two delta-crystallin/argininosuccinate lyase genes in lens, heart, and brain of chicken embryos.

Chicken delta-crystallin/argininosuccinate lyase (ASL), a major enzyme-crystallin of the embryonic lens, is encoded by two similar, tandemly arranged genes (delta 1 and delta 2). We show here by the polymerase chain reaction (PCR) and in situ hybridization that although the amount of mRNA for each of the delta-crystallins increases in the lens epithelial and fiber cells during development of the embryonic chicken, the delta 1 mRNA accumulates preferentially in the fiber cells. The delta 1/delta 2 mRNA ratio actually decreased from 16.5 +/- 7 to 6.5 +/- 1 in the central epithelial cells while it increased from 20 +/- 10 to 95 +/- 5 in the fibers between 6 and 14 days of development. By contrast, the heart and brain of 4- to 8-day-old embryonic chickens showed 10(3) to 10(4) times less delta-crystallin mRNA per microgram of total RNA than the lens, with a delta 1/delta 2 mRNA ratio of only 0.20 to 0.30. The tissue-specific differences in the relative expression of the two delta-crystallin genes suggest that the delta 2 polypeptide is principally responsible for ASL activity and that the delta 1 polypeptide is specialized for lens transparency. The trace amounts of delta 1 mRNA in the heart and brain raise the possibility that the delta 1 polypeptide contributes to or modulates ASL activity of the native tetrameric protein. Transfection experiments in which we used the pSVOCAT plasmid demonstrated that both delta-crystallin genes contain an enhancer in their third intron. The promoter and enhancer of each delta-crystallin gene were functionally comparable in the pSVOCAT plasmid when tested in primary embryonic lens epithelial cells, suggesting that the differential expression of the two delta-crystallin genes in the lens requires additional cis-regulatory sequences, post-transcriptional mechanisms, or both.

Animals↗