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PubMed1993

Differential synthesis of type 1 and type 2 desmocollin mRNAs in human stratified epithelia.

Epithelial cells are tightly connected by various kinds of junctions, of which the desmosomes (maculae adhaerentes) are particularly prominent. The desmosomes are characterized by two subgroups of constitutive transmembrane glycoproteins, the desmogleins and the desmocollins, which have been identified as specific members of the larger multigene family of CAMs of the cadherin category. Following our recent observation in bovine tissues that different desmoglein and desmocollin genes can be expressed in different cell types (Koch, P.J. et al., Proc. Natl. Acad. Sci. USA 89:353-357, 1992), we have now isolated cDNAs encoding human desmocollins type 1 and type 2. The complete sequence of human type 1 desmocollin has been determined and identified by its homology to the corresponding bovine gene product. Using in situ hybridization on sections through frozen human tissues, we show that mRNAs for type 2 desmocollin are synthesized in various stratified epithelia such as epidermis, esophagus and exocervix, whereas type 1 desmocollin was detected in appreciable amounts only in epidermis. In addition, a striking difference has been observed within the epidermis, where type 2 desmocollin mRNA can be detected in several basal layers of living cells but type 1 desmocollin mRNA is restricted to suprabasal layers. The possible functional involvement of desmocollins in the differentiation of stratified tissues is discussed and the potential value of molecular probes for desmosomal cadherins in tumor diagnosis is emphasized.

Amino Acid Sequence↗
PubMed1999

Molecular evolution of a developmental pathway: phylogenetic analyses of transforming growth factor-beta family ligands, receptors and Smad signal transducers.

Intercellular signaling by transforming growth factor-beta (TGF-beta) proteins coordinates developmental decisions in many organisms. A receptor complex and Smad signal transducers are required for proper responses to TGF-beta signals. We have taken a phylogenetic approach to understanding the developmental evolutionary history of TGF-beta signaling pathways. We were interested in detecting evolutionary influences among the physically interacting multigene families encoding TGF-beta ligands, receptors, and Smads. Our analyses included new ligands and Smads identified from genomic sequence as well as the newest published family members. From an evolutionary perspective we find that (1) TGF-beta pathways do not predate the divergence of animals, plants, and fungi; (2) ligands of the TGF-beta/activin subfamily likely originated after the divergence of nematodes and arthropods; (3) type I receptors from Caenorhabditis elegans are distinct from other receptors and may reflect an ancestral transitional state between type I and type II receptors; and (4) the Smad family appears to be evolving faster than, and independently of, ligands and receptors. From a developmental perspective we find (1) numerous phylogenetic associations not previously detected in each multigene family; (2) that there are unidentified pathway components that discriminate between type I and type II receptors; (3) that there are more Smads to be discovered in Drosophila and mammals; and (4) that the number of C-terminal serines is the best predictor of a Smad's role in TGF-beta signal transduction. We discuss these findings with respect to the coevolution of physically interacting genes.

Amino Acid Sequence↗
PubMed1986

Actin and myosin multigene families: their expression during the formation and maturation of striated muscle.

The initial formation of skeletal muscle fibers is accompanied by the expression of muscle-type actin and myosin genes. During subsequent maturation of muscle fibers in vivo, developmental changes in the fetal/adult isoforms of these proteins occur. Skeletal muscle-specific transcripts coding for different myosin heavy chains accumulate sequentially both in vivo and in vitro. A genetic analysis demonstrates that these genes are clustered, implicating cis-acting regulatory factors. In contrast, actin and myosin light chain genes are dispersed in the mouse genome. These gene families show a different developmental "strategy": Genes expressed in adult cardiac tissue are coexpressed with the corresponding skeletal muscle sequence during fetal development. This phenomenon also occurs in adult tissue. Under conditions of cardiac overload, adult rat hearts accumulate skeletal actin mRNA and cardiac actin transcripts. In some mouse lines, a mutant cardiac actin gene locus is present. The presence of a second active upstream promoter at this locus depresses transcription of the bone fide gene, resulting in low levels of mature cardiac actin mRNA. In this situation skeletal actin gene transcripts accumulate. Genes expressed in the same fetal or adult muscle phenotype are not linked, suggesting that their coexpression is regulated by transacting factors. The promoter regions of such genes in the mouse have no common characteristics of primary structure with the exception of an E1A-type enhancer core sequence, which has a conserved 5' flanking element, seen for actin and myosin light chain genes. Reintroduction of these promoter regions into muscle cells provides a functional test for such potential regulatory sequences.

Actins↗
PubMed1994

Ly-49 multigene family expressed by IL-2-activated NK cells.

The susceptibility of a target cell to killing by NK cells is inversely correlated with target cell expression of MHC class I molecules. We have recently demonstrated that a murine NK cell surface molecule, Ly-49, is a primary determinant of IL-2-activated NK cell specificity by apparently acting as an inhibitory receptor. Ly-49 seems to interact with polymorphic regions of certain MHC class I molecules on target cells, yet is expressed only by a subset (15 to 20%) of NK cells. If the interaction between Ly-49 and MHC class I represents a paradigm for understanding IL-2-activated NK cell specificity and putative inhibitory IL-2-activated NK cell receptors, these effector cells should express other molecules, perhaps related to Ly-49, that provide the inhibitory receptor function. We now report the isolation of cDNAs, encoding polypeptides related to Ly-49, from a CD3-, IL-2-activated NK cell library. Full length PCR products were also cloned and sequenced, confirming expression in IL-2-activated NK cells. These cDNAs were homologous to the Ly-49 cDNA and seem to be derived from distinct genes. The new cDNAs encode type II integral membrane proteins having lectin superfamily homology and 66 to 79% amino acid identity with Ly-49A. In contrast to previous reports, these cDNAs cannot be allelic variants because they were all isolated from C57BL/6-derived cells. On the basis of nucleotide homology, the cDNAs could be segregated into five groups; one with Ly-49 itself (now termed Ly-49A) and four others containing distinct sequences. One of the new groups comprised three cDNAs that shared identical sequences, but differed from one another by deletions or insertions of short DNA segments in the predicted extracellular region of the polypeptides. Thus, IL-2-activated NK cells express mRNAs for multiple, Ly-49-related molecules.

Animals↗
PubMed1989

Variations of a Y chromosome repeated sequence across subspecies of Mus musculus.

The complex species Mus musculus is widespread in Eurasia and consists of four parapatric genetical entities (subspecies) that have recently radiated. Two of them (M. m. domesticus and M. m. musculus) are known to interact through a narrow zone of hybridisation across which autosomal and mitochondrial exchanges are very limited and Y chromosome exchange is absent. We extend here the study of this group by the genetical analysis of 22 Asian strains of various origins (China, Korea, Japan, Taiwan, Philippines and Indonesia). A survey of protein variation at ten polymorphic loci confirmed that these animals belong to either the subspecies M. m. musculus (northern type in Asia, ranging westwards to Eastern Europe) or to M. m. castaneus (southern Asian type) and revealed a certain degree of intergradation between the two taxa. Y chromosome variations were assessed in these strains using a Y specific DNA probe representing part of a small multigene family and also in four M. m. domesticus (the Western European house mouse) strains of various origins and one M. m. bactrianus (from Pakistan). Musculus and castaneus were identically monomorphic for one type of organisation of this Y repeated family, while domesticus and bactrianus were very similar to each other, showing slightly different types of organisation. Introgression of a bactrianus Y chromosome into the territory of castaneus was found in Indonesia. The present distribution of the Y types among the four subspecies is not phylogenetically concordant with the known distributions of autosomal and mitochondrial variants.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed2001

A novel cluster of lectin-like receptor genes expressed in monocytic, dendritic and endothelial cells maps close to the NK receptor genes in the human NK gene complex.

The NK gene complex is a region on human chromosome 12 containing several families of lectin-like genes including the CD94 and NKG2 NK receptor genes. We report here that the region telomeric of CD94 contains in addition to the LOX-1 gene the novel human DECTIN-1 and the CLEC-1 and CLEC-2 genes within about 100 kb. Sequence similarities and chromosomal arrangement suggest that these genes form a separate subfamily of lectin-like genes within the NK gene complex. DECTIN-1 is selectively expressed in dendritic cells and to a lower extent in monocytes and macrophages. mRNA forms with and without a stalk exon are observed. During functional maturation of dendritic cells the level of DECTIN-1 mRNA is down-regulated several-fold. CLEC-1 is found to be not only expressed in dendritic cells, but also in endothelial cells and in the latter aspect resembles the LOX-1 gene. Whereas recombinant full-length DECTIN-1 and LOX-1 are transported to the cell surface, CLEC-1 proteins accumulate in perinuclear compartments. We propose that this family of lectin-like genes encodes receptors with important immune and/or scavenger functions in monocytic, dendritic and endothelial cells.

Amino Acid Sequence↗
PubMed1977

Genetic control of contact sensitivity to oxazolone in inbred, H-2 congenic and intra-H-2 recombinant strains of mice.

Delayed-type hypersensitivity (DTH) to 2-phenyl-4-ethoxymethylene-5-oxazolone (oxazolone) was found to be under multigenic control in inbred, H-2 congenic and intra-H-2 recombinant strains of mice. A high response was associated with haplotypes H-2d,a,k and low response with haplotype H-2b. DTH to oxazolone was high or intermediate in different F1 hybrids of high and low responder mice. In F2 and backcross generations a higher response was associated with the "dd", than with "bb" phenotype, while intermediate response was found in the heterozygote "db" mice. A study of H-2 recombinant strains suggests that a gene controlling the DTH response maps in the I-B subregion of the H-2 complex. The response was significantly modified by gene(s) which are not linked to the H-2 complex and have not been mapped. Since congenitally athymic nude (nu/nu) mice did not respond to oxazolone, this contact sensitivity is belived to be a T cell-dependent immune response.

Administration, Topical↗
PubMed1999

A novel family of Ig-like receptors for HLA class I molecules that modulate function of lymphoid and myeloid cells.

We review what is presently known about structure, cellular distribution, biochemical characteristics, and function of a new family of human cell-surface receptors referred to as immunoglobulin-like transcripts (ILTs), leukocyte Ig-like receptors (LIRs), or monocyte/macrophage Ig-like receptors (MIRs). These receptors are genetically, structurally, and functionally related to a group of natural killer (NK) cell receptors for HLA class I molecules known as killer cell Ig-like receptors (KIRs). Distinct ILT/LIR/MIR isotypes are differentially expressed on lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes; at least some of them recognize HLA class I molecules. Whereas some isotypes either inhibit or induce cell activation, others may be secreted as soluble receptors. ILT/LIR/MIR receptors may allow all immune cells to monitor class I expression on other cells and to respond in its absence, just as NK cells do. In addition, they may contribute to homeostasis by establishing activation thresholds that can be overcome only by relevant triggering stimuli and not by bystander cells.

Antibodies, Monoclonal↗
PubMed1997

Spontaneous occurrence of early region 1A reiteration mutants of type 5 adenovirus in persistently infected human T-lymphocytes.

Mutants of type 5 adenovirus (Ad5) with reiterated DNA sequences in the E1a region appeared in a human T-lymphocyte cell line, Molt-4, persistently infected with H5sub304, a deletion/substitution mutant that has a wild-type phenotype in viral replication. Endonuclease analyses and DNA sequencing revealed DNA reiteration in each mutant. In the four representative mutants investigated, the DNA reiterations all started within a six-base-pair consensus sequence, G(or C)CTGTG, located in the second exon of the E1a region (at nt 1333, 1367, or 1419). There was not any DNA homology between the breakpoints in the second exon and the inserting sequences (starting at nt 532, 710, or 792). Northern analyses suggested that the reiterated splicing sites of the representative mutants were all used in RNA splicing, and the closest donor and recipient joints were used most frequently. These observations imply that during persistent infection Ad5 underwent spontaneous mutations by sequence-specific breakage and nonhomologous end-end joining recombination events. These E1a reiteration mutants could be propagated in HeLa, A549, and KB cells; they were genetically stable; and they killed CREF cells at a strikingly high frequency. Preliminary observations tend to correlate this CREF cell killing with the accumulation of the early viral proteins and/or viral DNA in the infected cells. This degree of cell damage was not observed in Ad5wt or H5sub304 infection of CREF cells. The observed E1a reiterations provide a model to gain insight into understanding the evolutionary events of some, if not all, adenovirus types during many years of symbiotic, persistent relationship in human tonsils and adenoids and possibly other lymphoid organs.

Adenovirus E1A Proteins↗
PubMed1992

Molecular characterization of type 1 serine/threonine phosphatases from Brassica oleracea.

We describe the isolation of cDNA clones encoding type 1 serine/threonine protein phosphatase (PP1) from Brassica oleracea stigmas. We demonstrate that PP1 form a multigene family in Brassica. Within their most conserved domain, these phosphatases are 80-90% identical at the amino acid level. One cDNA (BoPP1) was found to encode a protein that shows 78-80% sequence identity to maize, rabbit, and yeast PP1. The accumulation of BoPP1 mRNA is developmentally regulated. Varying levels of BoPP1-homologous transcripts were detected in leaves, cotyledons, pistils, anthers and roots. In addition, distinct species of BoPP1 transcripts accumulated at different stages of Brassica microspore development, and mature trinucleate microspores contained a unique BoPP1 mRNA species not found at other stages of the plant's life cycle. Lastly, we show by genomic Southern blots that the Brassica genome might contain homologues of the mammalian PP1 inhibitor-1.

Amino Acid Sequence↗
PubMed1994

Pattern and degree of methylation in ribosomal RNA genes of Cucurbita pepo L.

Methylation with respect to its degree and distribution throughout the 18S, 5.8S and 25S rRNA gene clusters (rDNA) and within single rDNA repeats in seedlings of the higher plant Cucurbita pepo L. (zucchini) was investigated. In this plant, which is characterized by several thousand repeats, at least 70% are completely or nearly completely methylated in CpGs and to a lower degree in CpNpGs. Detailed methylation analysis revealed that a fraction of about 3-4% of all repeats is hypomethylated near the transcription initiation site (TIS) which may indicate the fraction of active repeats in C. pepo. However, a different fraction (3-4% of all repeats) which is not methylated in all sites tested (including those at the TIS) is present in C. pepo and may thus represent active but differentially methylated rDNA. The results are discussed in context of recent models on methylation and gene activity.

DNA, Ribosomal↗
PubMed1993

Characterization of a third simple tandem repeat polymorphism in the human glucokinase gene.

Recent studies have implicated mutations in the glucokinase gene as a cause of early-onset Type 2 (non-insulin-dependent) diabetes mellitus. Two simple tandem repeat DNA polymorphisms have been identified in this gene and used for genetic studies. However, their heterozygosity is relatively low and not all families are informative for linkage with these markers. Here we report the characterization of a third simple tandem repeat polymorphism that can be used for genetic studies.

Base Sequence↗
PubMed1992

The gene structure of Xenopus nuclear lamin A: a model for the evolution of A-type from B-type lamins by exon shuffling.

Nuclear lamins are intermediate filament (IF) type proteins that form a fibrillar network underlying the inner nuclear membrane. The existence of multiple subtypes of lamins in vertebrates has been interpreted in terms of functional specialization during cell division and differentiation. The structure of a gene encoding an A-type lamin of Xenopus laevis was analysed. Comparison with that of a B-type lamin of the same species shows remarkable conservation of the exon/intron pattern. In both genes the last exon, only 9-12 amino acids in length, encodes the complete information necessary for membrane targeting of lamins, i.e. a ras-related CaaX motif. The lamin A specific extension of the tail domain is encoded by a single additional exon. The 5' boundary of this exon coincides with the sequence divergence between human lamins A and C, for which an alternative splice mechanism had previously been suggested. Arguments are presented suggesting that B-type lamins represent the ancestral type of lamins and that A-type lamins derived there from by exon shuffling. The acquisition of the new exon might explain the different fates of A- and B-types lamins during cell division.

Amino Acid Sequence↗
PubMed1991

Cloning and structural analysis of two distinct families of ovine interferon-alpha genes encoding functional class II and trophoblast (oTP) alpha-interferons.

Ovine trophoblast protein (oTP) is a polypeptide secreted by ovine trophectoderm from day 11 to 21, which plays a key role in maternal recognition of pregnancy. Structural analyses established that oTP shares extensive homology with class II alpha-interferon (IFN-alpha II) subfamily. Previous screening of an ovine genomic DNA library probed with an oTP cDNA incidently resulted in the isolation of a functional IFN-alpha II gene and two relevant pseudogenes, as shown by sequence analysis and study of expression in eukaryotic COS cells. The expected oTP gene together with a cognate pseudogene was successfully isolated from the series of clones selected from another genomic library probed with the oTP cDNA, using two specific oligonucleotides, each one complementary to a region of oTP cDNA with little homology with the IFN-alpha II gene and related pseudogenes. Southern blotting of ovine genomic DNA indicated the existence of at least five trophoblast IFN-alpha genes or pseudogenes. Nucleotide sequence comparisons showed that the oTP gene exhibits a higher homology (90%) with bovine trophoblast IFN gene (Stewart et al. (1990) J. Mol. Endocrinol. 4, 275-282) than with oIFN-alpha II gene (70%), thus providing evidence that embryonic IFNs constitute a distinct subfamily of IFN-alpha s.

Amino Acid Sequence↗
PubMed1992

Correlation between insertion mutant activities and amino acid sequence identities of the TaqI and TthHB8 restriction endonucleases.

A two-codon insertion mutagenesis method has been generalized. Over two dozen insertion mutants throughout the gene encoding TaqI restriction endonuclease were constructed and activity was characterized. All mutants with activity either cleaved or nicked the canonical T decreases CGA recognition sequence. Some insertion mutants created duplication of gene regions, termed Gemini proteins, which still retained activity. The correlation between mutants with poor activity and the regions of shared amino acid identity between the isoschizomeric TaqI and TthHB8I suggests these regions are involved in DNA recognition and/or catalysis.

Amino Acid Sequence↗
PubMed2006

Regulated expression of FLRT genes implies a functional role in the regulation of FGF signalling during mouse development.

Within the mammalian genome, there are many multimember gene families that encode membrane proteins with extracellular leucine rich repeats which are thought to act as cell adhesion or signalling molecules. We previously showed that the members of the NLRR gene family are expressed in a developmentally restricted manner in the mouse with NLRR-1 being expressed in the developing myotome. The FLRT gene family shows a similar genomic layout and predicted protein secondary structure to the NLRRs so we analysed expression of the three FLRT genes during mouse development. FLRTs are glycosylated membrane proteins expressed at the cell surface which localise in a homophilic manner to cell-cell contacts expressing the focal adhesion marker vinculin. Each member of the FLRT family has a distinct, highly regulated expression pattern, as was seen for the NLRR family. FLRT3 has a provocative expression pattern during somite development being expressed in regions of the somite where muscle precursor cells migrate from the dermomyotome and move into the myotome, and later in myotomal precursors destined to migrate towards their final destination, for example, those that form the ventral body wall. FLRT3 is also expressed at the midbrain/hindbrain boundary and in the apical ectodermal ridge, regions where FGF signalling is known to be important, suggesting that the role for FLRT3 in FGF signalling identified in Xenopus is conserved in mammals. FLRT1 is expressed at brain compartmental boundaries and FLRT2 is expressed in a subset of the sclerotome, adjacent to the region that forms the syndetome, suggesting that interaction with FGF signalling may be a general property of FLRT proteins. We confirmed this by showing that all FLRTs can interact with FGFR1 and FLRTs can be induced by the activation of FGF signalling by FGF-2. We conclude that FLRT proteins act as regulators of FGF signalling, being induced by the signal and then able to interact with the signalling receptor, in many tissues during mouse embryogenesis. This process may, in part, be dependent on homophilic intercellular interactions between FLRT molecules.

3' Untranslated Regions↗
PubMed1997

Molecular cloning and characterisation of a developmentally regulated putative metallopeptidase present in a host protective extract of Haemonchus contortus.

Antisera from lambs immunised with the Haemonchus contortus integral membrane protein complex, Haemonchus galactose-containing glycoprotein (H-gal-GP), the lambs being refractory to subsequent challenge, were used to identify several clones from an adult H. contortus lambda gt11 cDNA library. Using gene-specific oligonucleotide primers in conjunction with primers directed to a conserved nematode Spliced Leader (SL) sequence and to the polyA+ tail of mRNA, the remaining 5' and 3' sequences of one of these clones, metallopeptidase-1 (MEP1), were amplified. The 2.4 kb full-length coding sequences was subsequently amplified in a single reaction. Sequence analysis identified MEP1 as encoding a putative zinc metallopeptidase, which shared limited homology with the mammalian type II integral membrane protein neutral endopeptidase (NEP). Southern blotting indicated that MEP1 belonged to a multigene family. MEP1 was expressed in bacteria as a glutathione-S-transferase (GST) fusion protein, and a specific antiserum raised in sheep. This antiserum recognised several polypeptide components of H-gal-GP. Immunolocalisation studies showed that MEP1 encoded a protein located on the luminal surface of the nematode gut. Both MEP1 mRNA and protein are developmentally regulated with expression being limited to the blood-feeding stages of H. contortus.

Amino Acid Sequence↗