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PubMed1990

Schizosaccharomyces pombe ras1 and byr1 are functionally related genes of the ste family that affect starvation-induced transcription of mating-type genes.

We have further investigated the function of the ras1 and byr1 genes, which were previously shown to be critical for sexual differentiation in fission yeast cells. Several physiological similarities between strains containing null alleles of these genes supports the idea that ras1 and byr1 are functionally closely related. Furthermore, we have found that byr1 is allelic to ste1, one of at least 10 genes which when mutated can cause sterility. Since ras1 had previously been found to be allelic to ste5, both ras and byr genes are now clearly shown to be a part of the ste gene family, thus confirming their close functional relationship. The observation that the mating-type loci could overcome the sporulation block of ras1 and byr1 mutant strains prompted investigation of the role of the ras-byr pathway in the induction of the mating-type gene transcripts upon nitrogen starvation. By Northern analysis of RNA preparations from strains carrying wild-type or mutant ras1 alleles and grown to different stages of the growth cycle, we have shown that ras1 plays an important role in inducing the Pi transcript of the mating-type loci and the mei3 gene transcript. These observations provide a molecular basis for the role of the ste gene family, including ras1 and byr1, in meiosis and indicate that further characterization of other ste genes would be very useful for elucidating the mechanism of ras1 function in fission yeast cells.

Alleles↗
PubMed2004

Correlating function and gene expression of individual basal ganglia neurons.

Functional studies at the level of individual neurons have greatly contributed to our current understanding of basal ganglia function and dysfunction. However, identification of the expressed genes responsible for these distinct neuronal phenotypes is less advanced. Qualitative and quantitative single-cell gene-expression profiling, combined with electrophysiological analysis, allows phenotype-genotype correlations to be made for individual neurons. In this review, progress on gene-expression profiling of individual, functionally characterized basal ganglia neurons is discussed, focusing on ion channels and receptors. In addition, methodological issues are discussed and emerging novel techniques are introduced that will enable a genome-wide comparison of function and gene expression for individual neurons.

Animals↗
PubMed1998

Enhanced and specific gene expression via tissue-specific production of Cre recombinase using adenovirus vector.

A tissue-specific promoter is potentially valuable for the study of specific gene function and for gene therapy, as it permits a linked cytotoxic or any other gene to be expressed specifically in target cells. The expression levels of such promoters are generally low, and we have therefore developed a novel and general method to enhance the expression level of a tissue-specific promoter while maintaining specificity. We constructed a "regulator" recombinant adenovirus (rAd) producing the site-specific recombinase Cre under the control of the hepatocarcinoma-specific alpha-fetoprotein (AFP) promoter. The rAd was infected to AFP-producing cells together with a "target" rAd containing a Cre-activating potent expression unit. In in vitro experiments, the double infection method gave about 50-fold higher expression than the single rAd infection directly driven by the AFP promoter, while maintaining strict specificity to AFP-producing cells. The enhanced and specific expression was also observed in in vivo tumor models. This method may contribute not only to the establishment of specific gene therapies but also to basic study for elucidating cell-type specific gene functions.

Adenoviridae↗
PubMed1998

African swine fever virus NL gene is not required for virus virulence.

Previously, we described a highly conserved nonessential African swine fever virus (ASFV) right variable region gene, NL. Deletion of NL from the European pathogenic isolate E70 resulted in almost complete attenuation of the virus in domestic swine. To study gene function further, NL gene deletion mutants were constructed from two pathogenic African ASFV isolates, Malawi Lil-20/1 (Mal) and Pretoriuskop/96/4 (Pr4). Unexpectedly, both Mal (Mal-deltaNL) and PR4 (Pr4deltaNL) null mutants remained highly virulent when inoculated in swine. Mal-deltaNL exhibited a disease and virulence phenotype indistinguishable from its revertant, Mal-NLR, which caused 100% mortality. Mortality among Pr4deltaNL-infected animals was also high; however, a significant delay in onset of fever and viraemia and in time to death was observed. These data indicate that NL gene function is not required for ASFV virulence and that other yet-to-be identified viral determinants perform significant virulence functions in these African field isolates.

African Swine Fever Virus↗
PubMedDate not supplied

Marker-assisted study of genetic background and gene-targeted locus modifiers in lymphopoietic phenotypes.

Forward and reverse genetic approaches facilitate the molecular dissection of individual gene functions and the integration of individual gene functions into multi-gene processes in the context of the whole organism. Variations in mutant phenotypes due to genetic background differences have been well documented through the analysis of mouse mutants. Nevertheless, recommendations concerning the assessment of genetic background as it impacts on phenotype, and utilization of genetic background differences to identify and integrate gene functions have been largely overlooked. Genetic background as it relates to immunological mutants will be discussed utilizing an Ets1-targeted allele to exemplify phenotypic variation due to background. Marker-assisted strategies for the identification of genetic modifiers, especially those linked to the targeted locus, will also be considered.

Animals↗
PubMedDate not supplied

Transgene regulation by the tetracycline-controlled transactivation system.

The tetracycline-controlled transactivation system is one of the most powerful tools for modifiable expression of exogenous genes. This system enables selective, stringent and quantitative regulation of transgenes in vitro and in vivo. By combining with antisense genes, ribozymes or genes encoding dominant negative mutants, it is also feasible to control certain endogenous gene functions. Combination with transgenic or 'gene knockout' technologies enables the generation of mice in which a certain gene function is conditionally reinforced or deleted. These sophisticated methods are useful for investigation of gene function during embryogenesis and in adult organs and for well-controlled gene therapy approaches. This article briefly outlines the concept of the tetracycline-regulated gene expression systems and addresses the current experience in kidney research.

Animals↗
PubMed2005

Two members of the Fxr gene family, Fmr1 and Fxr1, are differentially expressed in Xenopus tropicalis.

The Fxr gene family is composed of three members, FMR1, FXR1 and FXR2. The FMR1 gene is involved in the fragile X syndrome, whereas for the other two members, no human disorder has been identified yet. An appropriate animal model to study in vivo gene function is essential to unravel the cellular function of the gene products FMRP, FXR1P and FXR2P, respectively. In Xenopus tropicalis both Fmr1 and Fxr1 were identified; however, unexpectedly Fxr2 was not. Here we describe the characterization of both Fmrp and Fxr1p in Xenopus tropicalis. Fmrp is expressed ubiquitously throughout the embryo during embryonic development, whereas Fxr1p shows a more tissue-specific expression particularly during late embryonic development. In adult frogs both proteins are highly expressed in most neurons of the central nervous system and in all spermatogenic cells in the testis. In addition, Fxr1p is also highly expressed in striated muscle tissue. Western blotting experiments revealed only one prominent isoform for both proteins using different tissue homogenates from adult frogs. Thus, for in vivo gene function studies, this relative simple animal model may serve as a highly advantageous and complementary model.

Amino Acid Sequence↗
PubMed2004

Distinguishing key biological pathways between primary breast cancers and their lymph node metastases by gene function-based clustering analysis.

In order to identify key biological pathways that can distinguish between primary breast cancers and their lymph node metastases, we employed gene expression profiling together with gene function-based clustering analysis. We first acquired gene expression profiles of 9 matched primary tumors and the corresponding metastases that contained at least 75% of tumor cells. Then, we applied a clustering algorithm to the preprocessed data. In order to focus on the most informative genes, we ranked all the genes individually based on their abilities to separate the primary breast tumor and metastases samples. Further, we separated these genes into six functional groups according to the Stanford SOURCE database: 'cell cycle,' 'apoptosis,' 'metabolism,' 'cell adhesion and migration,' 'signal transduction,' and 'transcriptional factor and DNA binding molecules.' Unsupervised clustering analysis using all of the 2,303 genes on the microarrays was not able to separate the primary and metastases samples. Clustering analysis using the most informative genes revealed that primary tumors were more tightly clustered, whereas the metastases samples were relatively heterogeneous. The clustering analysis with the genes belonging to different functional groups showed that different functional gene sets varied in their abilities to separate primary tumors and their metastases. Marked separations were found with genes involved in metabolism, signal transduction, cell cycle, and transcriptional factor and DNA binding molecules. In contrast, apoptosis and cell adhesion and migration genes did not provide a clear separation of the two groups of samples. These results suggest that metastatic cells have different metabolism and signal transduction activities, regulated by transcriptional events, from the primary tumor cells. The results also suggest that the altered cell adhesion and migration potentials that are required for tumors to metastasize already exist in the primary tumors as a whole.

Biomarkers, Tumor↗
PubMed2005

(TG/CA)n repeats in human gene families: abundance and selective patterns of distribution according to function and gene length.

BACKGROUND: Creation of human gene families was facilitated significantly by gene duplication and diversification. The (TG/CA)n repeats exhibit length variability, display genome-wide distribution, and are abundant in the human genome. Accumulation of evidences for their multiple functional roles including regulation of transcription and stimulation of recombination and splicing elect them as functional elements. Here, we report analysis of the distribution of (TG/CA)n repeats in human gene families. RESULTS: The 1,317 human gene families were classified into six functional classes. Distribution of (TG/CA)n repeats were analyzed both from a global perspective and from a stratified perspective based on their biological properties. The number of genes with repeats decreased with increasing repeat length and several genes (53%) had repeats of multiple types in various combinations. Repeats were positively associated with the class of Signaling and communication whereas, they were negatively associated with the classes of Immune and related functions and of Information. The proportion of genes with (TG/CA)n repeats in each class was proportional to the corresponding average gene length. The repeat distribution pattern in large gene families generally mirrored the global distribution pattern but differed particularly for Collagen gene family, which was rich in repeats. The position and flanking sequences of the repeats of Collagen genes showed high conservation in the Chimpanzee genome. However the majority of these repeats displayed length polymorphism. CONCLUSION: Positive association of repeats with genes of Signaling and communication points to their role in modulation of transcription. Negative association of repeats in genes of Information relates to the smaller gene length, higher expression and fundamental role in cellular physiology. In genes of Immune and related functions negative association of repeats perhaps relates to the smaller gene length and the directional nature of the recombinogenic processes to generate immune diversity. Thus, multiple factors including gene length, function and directionality of recombinogenic processes steered the observed distribution of (TG/CA)n repeats. Furthermore, the distribution of repeat patterns is consistent with the current model that long repeats tend to contract more than expand whereas, the reverse dynamics operates in short repeats.

Animals↗
PubMed1996

Embryonic patterning mutants of Tribolium castaneum.

The identification and analysis of genes controlling segmentation in Drosophila melanogaster has opened the way for understanding similarities and differences in mechanisms of segmentation among the insects. Homologues of Drosophila segmentation genes have been cloned and their expression patterns have been analyzed in a variety of insects, revealing that the patterns of expression of many genes are conserved. Conserved expression patterns do not, however, necessarily reflect conserved gene function. To address gene function, we have conducted a screen for mutations that alter embryonic patterning of the beetle, Tribolium castaneum. One of the mutations isolated, godzilla, affects early steps in the segmentation process in the whole animal, like Drosophila pair-rule mutants. Another mutation, jaws, is novel: it caused both a dramatic homeotic transformation in the thorax and first abdominal segment as well as a deletion of most of the segments of the abdomen. In Tribolium and other intermediated germ band insects, the anterior segments of the embryo are determined in the syncytium of the blastoderm, whereas the abdominal segments proliferated in the cellular environment. Both the godzilla and jaws mutations affect segments that are formed in the syncytium differently from those that are formed after cellularization. These regionally specific phenotypes may reflect the different patterning mechanisms that must be employed by the anterior and posterior regions of an intermediated germ insect.

Animals↗
PubMed2005

Virus-induced gene silencing-based functional characterization of genes associated with powdery mildew resistance in barley.

We successfully implemented virus-induced gene silencing (VIGS) in barley (Hordeum vulgare) for the functional characterization of genes required for Mla13-mediated resistance toward the biotrophic barley pathogen Blumeria graminis f. sp. hordei. Initially, barley cultivars were screened for their ability to host the barley stripe mosaic virus (BSMV)-VIGS vector by allowing its replication and systemic movement without causing excessive symptoms. Phytoene desaturase silencing leading to photobleaching was used as a phenotypic marker alongside reverse transcription-PCR data to characterize the silencing response at the molecular level. Barley cultivar Clansman, harboring the Mla13 resistance gene, was chosen as the most suitable host for BSMV-VIGS-based functional characterization of Rar1, Sgt1, and Hsp90 in the Mla-mediated resistance toward powdery mildew. BSMV-induced gene silencing of these candidate genes, which are associated in many but not all race-specific pathways, proved to be robust and could be detected at both mRNA and protein levels for up to 21 d postinoculation. Systemic silencing was observed not only in the newly developed leaves from the main stem but also in axillary shoots. By examining fungal development from an incompatible mildew strain carrying the cognate Avr13 gene on plants BSMV silenced for Rar1, Sgt1, and Hsp90, a resistance-breaking phenotype was observed, while plants infected with BSMV control constructs remained resistant. We demonstrate that Hsp90 is a required component for Mla13-mediated race-specific resistance and that BSMV-induced VIGS is a powerful tool to characterize genes involved in pathogen resistance in barley.

Carrier Proteins↗
PubMed2003

Plant sphingolipids: structural diversity, biosynthesis, first genes and functions.

In mammals and Saccharomyces cerevisiae, sphingolipids have been a subject of intensive research triggered by the interest in their structural diversity and in mammalian pathophysiology as well as in the availability of yeast mutants and suppressor strains. More recently, sphingolipids have attracted additional interest, because they are emerging as an important class of messenger molecules linked to many different cellular functions. In plants, sphingolipids show structural features differing from those found in animals and fungi, and much less is known about their biosynthesis and function. This review focuses on the sphingolipid modifications found in plants and on recent advances in the functional characterization of genes gaining new insight into plant sphingolipid biosynthesis. Recent studies indicate that plant sphingolipids may be also involved in signal transduction, membrane stability, host-pathogen interactions and stress responses.

Animals↗
PubMed2000

A new genetic method for isolating functionally interacting genes: high plo1(+)-dependent mutants and their suppressors define genes in mitotic and septation pathways in fission yeast.

We describe a general genetic method to identify genes encoding proteins that functionally interact with and/or are good candidates for downstream targets of a particular gene product. The screen identifies mutants whose growth depends on high levels of expression of that gene. We apply this to the plo1(+) gene that encodes a fission yeast homologue of the polo-like kinases. plo1(+) regulates both spindle formation and septation. We have isolated 17 high plo1(+)-dependent (pld) mutants that show defects in mitosis or septation. Three mutants show a mitotic arrest phenotype. Among the 14 pld mutants with septation defects, 12 mapped to known loci: cdc7, cdc15, cdc11 spg1, and sid2. One of the pld mutants, cdc7-PD1, was selected for suppressor analysis. As multicopy suppressors, we isolated four known genes involved in septation in fission yeast: spg1(+), sce3(+), cdc8(+), and rho1(+), and two previously uncharacterized genes, mpd1(+) and mpd2(+). mpd1(+) exhibits high homology to phosphatidylinositol 4-phosphate 5-kinase, while mpd2(+) resembles Saccharomyces cerevisiae SMY2; both proteins are involved in the regulation of actin-mediated processes. As chromosomal suppressors of cdc7-PD1, we isolated mutations of cdc16 that resulted in multiseptation without nuclear division. cdc16(+), dma1(+), byr3(+), byr4(+) and a truncated form of the cdc7 gene were isolated by complementation of one of these cdc16 mutations. These results demonstrate that screening for high dose-dependent mutants and their suppressors is an effective approach to identify functionally interacting genes.

Amino Acid Sequence↗
PubMed2003

RNA interference in the moss Physcomitrella patens.

The moss Physcomitrella patens performs efficient homologous recombination, which allows for the study of individual gene function by generating gene disruptions. Yet, if the gene of study is essential, gene disruptions cannot be isolated in the predominantly haploid P. patens. Additionally, disruption of a gene does not always generate observable phenotypes due to redundant functions from related genes. However, RNA interference (RNAi) can provide mutants for both of these situations. We show that RNAi disrupts gene expression in P. patens, adding a significant tool for the study of plant gene function. To assay for RNAi in moss, we constructed a line (NLS-4) expressing a nuclearly localized green fluorescent protein (GFP):beta-glucuronidase (GUS) fusion reporter protein. We targeted the reporter protein with two RNAi constructs, GUS-RNAi and GFP-RNAi, expressed transiently by particle bombardment. Transformed protonemal cells are marked by cobombardment with dsRed2, which diffuses between the nucleus and cytoplasm. Cells transformed with control constructs have nuclear/cytoplasmic red fluorescence and nuclear green fluorescence. In cells transformed with GUS-RNAi or GFP-RNAi constructs, the nuclear green fluorescence was reduced on average 9-fold as soon as 48 h after transformation. Moreover, isolated lines of NLS-4 stably transformed with GUS-RNAi construct have silenced nuclear GFP, indicating that RNAi is propagated stably. Thus, RNAi adds a powerful tool for functional analysis of plant genes in moss.

Bryopsida↗
PubMed2001

Modularity in the gain and loss of genes: applications for function prediction.

Genes that are clustered on multiple genomes and are likely to functionally interact tend to be gained or lost together during genome evolution. Here, we demonstrate that exceptions to this pattern indicate relatively distant functional interactions between the encoded proteins. Hence, this can be used to divide predicted clusters of functionally interacting proteins into sub-clusters, and as such, to refine the prediction of their function and functional interactions.

Bacterial Proteins↗
PubMed1993

The mouse Hox-1.3 gene is functionally equivalent to the Drosophila Sex combs reduced gene.

To test whether the mouse Hox-1.3 gene is a cognate of the Drosophila Sex combs reduced (Scr) gene, we inserted a hsp 70-Hox-1.3 fusion gene into the Drosophila genome. Transgenic flies displayed Scr-like homeotic transformations after ectopic expression of Hox-1.3 induced by heat shock. In larvae, the thoracic segments T2 and T3 are transformed toward T1. In adults, head structures are dramatically disrupted, including transformation of antenna towards leg. Transformations are not the result of ectopic activation of the endogenous Scr gene. Rather, Hox-1.3 appears to directly regulate Scr target genes, as demonstrated by the ectopic activation of fork head by Hox-1.3. The results suggest that mouse Hox-1.3 cannot only substitute functionally for Drosophila Scr in the determination of external structures but also can participate in the regulatory hierarchy of insect organogenesis.

Amino Acid Sequence↗
PubMed2026

Emerging Principles in Spatial Functional Genomics.

Spatial transcriptomic and proteomic atlases have enabled mapping of gene programs within intact tissues, but these measurements remain largely descriptive and do not define the mechanisms controlling tissue biology. Pooled CRISPR screening provides scalable causal interrogation of gene function but remains largely confined to dissociated systems that lack spatial context. In vivo spatial functional genomics (SFG) bridges these approaches by integrating genetic perturbations with in situ transcriptomic and proteomic readouts to measure gene function within intact tissue ecosystems. By preserving spatial organization, SFG enables interpretation of perturbations through effects on cell-cell interactions, diffusible signals, multicellular niches, and tissue architecture. Here, we outline key design axes of SFG: perturbation strategy, barcoding strategy, and phenotypic readout. We discuss computational challenges, including spatial autocorrelation, neighborhood dependence, and context-aware null modeling, and highlight how SFG reveals non-cell-autonomous, architecture-dependent mechanisms of gene function, advancing toward predictive models of tissue organization and gene function.

Genomics↗
PubMed1999

Rapid hypothesis testing with Candida albicans through gene disruption with short homology regions.

Disruption of newly identified genes in the pathogen Candida albicans is a vital step in determination of gene function. Several gene disruption methods described previously employ long regions of homology flanking a selectable marker. Here, we describe disruption of C. albicans genes with PCR products that have 50 to 60 bp of homology to a genomic sequence on each end of a selectable marker. We used the method to disrupt two known genes, ARG5 and ADE2, and two sequences newly identified through the Candida genome project, HRM101 and ENX3. HRM101 and ENX3 are homologous to genes in the conserved RIM101 (previously called RIM1) and PacC pathways of Saccharomyces cerevisiae and Aspergillus nidulans. We show that three independent hrm101/hrm101 mutants and two independent enx3/enx3 mutants are defective in filamentation on Spider medium. These observations argue that HRM101 and ENX3 sequences are indeed portions of genes and that the respective gene products have related functions.

Alleles↗