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PubMed1993

In utero rearrangements in the trithorax-related oncogene in infant leukaemias.

The majority (approximately 75%) of infant acute leukaemias have a reciprocal translocation between chromosome 11q23 and one of several partner chromosomes. The gene at 11q23 (named MLL, ALL-1, HRX or HTRX-1; refs 2-6) has been cloned and shares homology with the Drosophila developmental gene trithorax. Rearrangements of this gene (called HRX here) occur in introns and cluster in a region of approximately 10 kb; individual patients have different breakpoints. Here we describe three pairs of infant twins with concordant leukaemia who each share unique (clonal) but non-constitutive HRX rearrangements in their leukaemic cells, providing evidence that the leukaemogenic event originates in utero and unequivocal support for the intra-placental 'metastasis' hypothesis for leukaemia concordance in twins.

Chromosomes, Human, Pair 11↗
PubMed1990

Cell motility is required for the transmission of C-factor, an intercellular signal that coordinates fruiting body morphogenesis of Myxococcus xanthus.

There are striking similarities between the developmental phenotypes of two different mutant classes of Myxococcus xanthus. The first class, mglA mutants, are nonmotile under all conditions tested. The second class, csgA mutants, are motile but belong to a class of signal-defective developmental mutants that cannot develop alone but will develop when mixed with intact wild-type cells. Nevertheless, both csgA and mglA mutants fail to aggregate properly or to sporulate when induced to form fruiting bodies. An mglA mutation and a csgA mutation affect expression of a panel of lacZ fusions to developmental genes in the same way, indicating that nonmotile cells and csgA cells arrest development at a similar stage. One explanation for the similarity of developmental phenotypes between these mutants is that motility is required for the csgA-mediated cell interaction. In support of this hypothesis, we report that C-factor, a protein purified from nascent wild-type fruiting bodies based on its ability to rescue csgA mutant fruiting body development, also rescues sporulation and expression of beta-galactosidase from developmentally controlled lacZ fusions in mglA strains, apparently without restoring their motility. Wild-type levels of active C-factor can be purified from mglA cells, yet intact mglA cells do not rescue csgA cells upon cell-cell mixing. Intact wild-type cells are unable to restore the sporulation and beta-galactosidase expression of mglA mutants. These results support the hypothesis that donor and responder cell motility is required for C-factor transmission between cells during development.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacterial Proteins↗
PubMed2004

A role for nuclear factor I in the intrinsic control of cerebellar granule neuron gene expression.

Nervous system formation requires the elaboration of a complex series of differentiation events in both a spatially and maturation-regulated manner. A fundamental question is how neuronal subtype specification and developmental gene expression are controlled within maturing neurons. The alpha6 subunit of the gamma-aminobutyric acid type A (GABA(A)) receptor (GABRA6) is preferentially expressed in cerebellar granule neurons and is part of an intrinsic program directing their differentiation. We have employed a lentiviral approach to examine the transcriptional mechanisms controlling neuronal subtype-selective expression of this gene. These studies demonstrated that nuclear factor I (NFI) proteins are required for both transgenic GABRA6 promoter activity as well as endogenous expression of this gene in cerebellar granule neurons. Chromatin immunoprecipitation also showed that NFI proteins are bound to the GABRA6 promoter in these cells in vivo. Furthermore, analyses of gene knockout mice revealed that Nfia is specifically required for normal expression of the GABRA6 gene in cerebellar granule neurons. NFI expression and DNA binding activity are highly enriched in granule neurons, implicating this transcription factor family in the neuronal subtype-selective expression of the GABRA6 gene. These studies define a new role for NFI proteins as neuronal subtype-enriched transcriptional regulators that participate in an intrinsic transcriptional program directing the differentiation of cerebellar granule neurons.

Animals↗
PubMed1986

Developmental control of gene expression of tryptophan 2,3-dioxygenase in neonatal rat liver.

The developmental change in gene expression of tryptophan 2,3-dioxygenase (EC 1.13.11.11) in rat liver was studied by dot-blot hybridization with cDNA of the enzyme as a probe. The mRNA of tryptophan oxygenase is not expressed in fetal liver, but is expressed very slightly 1 day after birth. Its expression increases first gradually until 12 days after birth and then rapidly, and reaches the adult level about 22 days after birth. On the other hand, mRNA of albumin in the liver, measured with its cDNA, increases rapidly in the late fetal period and reaches almost the adult level at the time of birth. Studies on in vitro transcription by the nuclear run-off technique showed that the developmental increases in the mRNAs of tryptophan oxygenase and albumin are caused by an increase in the rates of transcription of their genes. Treatment of rats with cortisol significantly increased the amount of tryptophan oxygenase mRNA in the liver from soon after birth. This treatment did not increase mRNA of albumin. It is suggested from these findings that the gene of tryptophan oxygenase is switched on as early as the first day after birth in the few differentiated hepatocytes present in the liver and that the number of these differentiated cells gradually increases during early postnatal development. Although injected glucocorticoid stimulated transcription of the gene of tryptophan oxygenase precociously during this period, presumably in vivo the activity of tryptophan oxygenase normally increases about 2 weeks after birth, because this is when the plasma concentrations of glucocorticoid and glucagon increase sufficiently to be effective.

Age Factors↗
PubMed2006

HoxB domain induction silences DNA replication origins in the locus and specifies a single origin at its boundary.

In multicellular organisms, changes in the DNA replication programme could act to integrate differentiation with cell division in various developmental and transcriptional contexts. Here, we have addressed the use of DNA replication origins during differentiation in the HoxB domain-a cluster of nine genes developmentally regulated in a collinear manner. In undifferentiated mouse P19 cells, we detected several DNA replication origins in the 100 kb HoxB locus, indicating a relaxed origin use when the locus is transcriptionally silent. By contrast, in retinoic-acid-induced differentiated cells, when HoxB transcription is activated, a general silencing of DNA replication origins occurs in the locus except one located downstream of Hoxb1, at the 3' boundary of the HoxB domain. Silencing of the replication origins is associated with histone hyperacetylation, whereas the active Hoxb1 origin persists as a hypoacetylated island. These findings provide direct evidence for the differentiated use of origins in HoxB genes, and we suggest that this regulation might contribute to the regulated expression of HoxB genes during development.

Acetylation↗
PubMed1989

Molecular basis for the regulation of cell fate by the lethal (2) giant larvae tumour suppressor gene of Drosophila melanogaster.

Tumour suppressor genes act as recessive determinants of cancer. Their function is required for normal cell growth and differentiation during development. When both alleles of these developmental genes are inactivated, cell growth becomes unrestricted. In Drosophila, a series of genes have been identified which when mutated produce tissue-specific tumours. Of these the lethal(2)giant larvae (l(2)gl) gene is the best studied. Homozygous l(2)gl mutations cause the development of malignant tumours in the brain and the imaginal discs. Genomic DNA from the l(2)gl locus has been cloned, introduced back into l(2)gl mutant animals by P-element-mediated transformation and shown to restore normal development. The nucleotide sequence of the l(2)gl gene (13.1 kb) has been determined, as well as the sequences of the two classes of transcripts. These transcripts encode two polypeptides of 127 kDa and 78 kDa, respectively. Both proteins have been immunologically identified. Analyses of the spatial distribution of both l(2)gl transcripts and proteins revealed that during early embryogenesis the l(2)gl gene is uniformly expressed in all cells and tissues. In late embryos, the l(2)gl expression becomes gradually restricted to tissues presenting no morphological or neoplastic alteration in the mutant animals. Further mosaic experiments pointed out that the critical period for the establishment of tumorigenesis is limited to early embryogenesis at a time when the l(2)gl expression is most intense in all cells.

Animals↗
PubMed1996

Cell-specific transcriptional regulation and reactivation of galectin-1 gene expression are controlled by DNA methylation of the promoter region.

The galectin-1 gene is developmentally regulated gene whose activity is strongly modulated during cell differentiation and transformation. We have previously shown that galectin-1 promoter constructs are highly active when transiently transfected in cells both expressing and not expressing the endogenous gene and that the basal activity is determined by a small region encompassing the transcription start site (from positions -50 to +50). We have now investigated the role of DNA methylation in galectin-1 gene expression. Southern blot analysis with HpaII and MspI endonucleases and sodium bisulfite analysis of genomic DNA from expressing and nonexpressing cell lines and cell hybrids showed a close correlation between gene activity and demethylation of the 5' region of the galectin-1 gene. We found that the galectin-1 promoter region is fully methylated, at every CpG site on both strands, in nonexpressing differentiated rat liver (FAO) and thyroid (PC C13) cells and unmethylated in the expressing undifferentiated liver (BRL3A) and thyroid transformed (PC myc/raf) cell lines. In addition, reactivation of the silent FAO alleles in FAO-human osteosarcoma (143tk-) hybrid cells is accompanied by a complete demethylation of the promoter region. Finally, when galectin-1 chloramphenicol acetyltransferase (CAT) promoter constructs were methylated in vitro by SssI methylase at every cytosine residue of the CpG doublets and transfected into mouse fibroblasts, the transcription of the CAT reporter gene was strongly inhibited.

Animals↗
PubMed2002

Genetic "code": representations and dynamical models of genetic components and networks.

Dynamical modeling of biological systems is becoming increasingly widespread as people attempt to grasp biological phenomena in their full complexity and make sense of an accelerating stream of experimental data. We review a number of recent modeling studies that focus on systems specifically involving gene expression and regulation. These systems include bacterial metabolic operons and phase-variable piliation, bacteriophages T7 and lambda, and interacting networks of eukaryotic developmental genes. A wide range of conceptual and mathematical representations of genetic components and phenomena appears in these works. We discuss these representations in depth and give an overview of the tools currently available for creating and exploring dynamical models. We argue that for modeling to realize its full potential as a mainstream biological research technique the tools must become more general and flexible, and formal, standardized representations of biological knowledge and data must be developed.

Animals↗
PubMed1992

C/EBP and c-JUN proteins activate the proximal enhancer of the developmentally regulated alpha-fetoprotein gene.

The expression of the alpha-fetoprotein (AFP) gene is developmentally regulated. Active transcription of this gene depends on a proximal enhancer sequence located between positions D-203 bp and -81 bp, upstream the initiation site. This enhancer contains several putative binding sites for transcription factors. By transfection experiments, we showed that the enhancer activity can be driven by interactions with two regulatory factors, namely C/EBP and c-JUN.

Base Sequence↗
PubMed1986

Retroviruses as tools for mammalian development.

Retroviruses have been used as probes for the study of mammalian development. Successful applications of this tool include (1) genetic labeling of cells for lineage studies in preimplantation and postimplantation development, (2) tagging important chromosomal regions of the mouse genome, (3) identifying genes that are expressed during early development, and (4) generating mutant mouse strains by insertional mutations that allow for molecular and functional analyses of developmental genes.

Animals↗
PubMed2004

The synaptic pathology of schizophrenia: is aberrant neurodevelopment and plasticity to blame?

Synaptic pathology is a feature of the brain in schizophrenia, denoted by alterations in the expression of synaptic proteins. In the absence of data indicative of neurodegenerative processes, the neuropathological features of schizophrenia suggest that the major pathogenic process in the disorder is one of aberrant development. Molecular evidence in support of a neurodevelopmental origin of schizophrenia has come from studies examining the expression of key developmental genes. However, as many of these genes are also involved in synaptic plasticity, their altered expression in schizophrenia also suggests that the disorder may be one of aberrant synaptic plasticity. The aim of this review is to explore whether aberrant development and synaptic plasticity may underlie the synaptic pathology of schizophrenia. It does this in two ways. First, studies in schizophrenia of the expression of two synaptic genes important in synaptic remodeling and plasticity are reviewed, changes in which may be indicative of aberrant synaptic plasticity in the disorder. Second, the possible relationship between the expression of genes involved in development and plasticity with that of presynaptic proteins is examined. Such a relationship, in combination with their altered expression in schizophrenia, may indicate whether developmental and plasticity-related processes may contribute to the synaptic pathology of the disorder. A brief discussion on the possible origins of the synaptic pathology of schizophrenia, and possible future studies, concludes the review.

Animals↗
PubMed1994

Cloning and characterization of the socA locus which restores development to Myxococcus xanthus C-signaling mutants.

The csgA gene produces an intercellular signal during fruiting body formation of the myxobacterium Myxococcus xanthus. Sporulating pseudorevertants were isolated to allow us to understand the mechanism by which CsgA is perceived by cells and used to regulate developmental gene expression. Two strains, LS559 and LS560, which have closely linked transposon insertions, soc-559 (formerly csp-559) and soc-560 (formerly csp-560), respectively, regained all the developmental behaviors lost by the csgA mutation including the ability to ripple, form fruiting bodies, and sporulate. The sequence analysis of the socA locus revealed that there are three putative protein-coding regions, designated socA1, socA2, and socA3. The deduced amino acid sequence of socA1 exhibits characteristics of the short-chain alcohol dehydrogenase family. The deduced amino acid sequence of socA2 shares 48% identity with the frdD gene product of the frd operon in Proteus vulgaris which anchors fumarate reductase to the membrane. The deduced amino acid sequence of socA3 does not show homology to any known proteins. Genotypic complementation, Northern (RNA) blotting, DNA sequence analysis, and the pattern of gene expression all suggest that these three genes are polycistronic. Since the socA mutations effectively bypass CsgA, the question of why csgA is maintained in M. xanthus was examined by studying the long-term stability of socA spores. Unlike the wild type, socA mutant spores germinated on starvation agar. Transmission electron micrographs of spore thin sections revealed that germination is not due to an obvious structural deficiency of the socA spores. These results suggest that the ability of socA myxospores to survive long periods under unfavorable environmental conditions is severely comprised. Therefore, soxA appears to be essential for the development of M. xanthus.

Amino Acid Sequence↗
PubMed2005

Characterization of novel GPCR gene coding locus in amphioxus genome: gene structure, expression, and phylogenetic analysis with implications for its involvement in chemoreception.

Chemosensation is the primary sensory modality in almost all metazoans. The vertebrate olfactory receptor genes exist as tandem clusters in the genome, so that identifying their evolutionary origin would be useful for understanding the expansion of the sensory world in relation to a large-scale genomic duplication event in a lineage leading to the vertebrates. In this study, I characterized a novel GPCR (G-protein-coupled receptor) gene-coding locus from the amphioxus genome. The genomic DNA contains an intronless ORF whose deduced amino acid sequence encodes a seven-transmembrane protein with some amino acid residues characteristic of vertebrate olfactory receptors (ORs). Surveying counterparts in the Ciona intestinalis (Asidiacea, Urochordata) genome by querying BLAST programs against the Ciona genomic DNA sequence database resulted in the identification of a remotely related gene. In situ hybridization analysis labeled primary sensory neurons in the rostral epithelium of amphioxus adults. Based on these findings, together with comparison of the developmental gene expression between amphioxus and vertebrates, I postulate that chemoreceptive primary sensory neurons in the rostrum are an ancient cell population traceable at least as far back in phylogeny as the common ancestor of amphioxus and vertebrates.

Amino Acid Sequence↗
PubMed2001

Developmental potency of cultured pineal cells: an approach to pineal developmental biology.

The pineal organ is still an enigma in regard to its developmental and phylogenetic origin. Little is known of the mechanism involved in determination and differentiation of pineal cells and virtually no studies have been done on the induction and tissue interactions during pinealogenesis. Interest is also centered on the evolutional transformation in structure and function, which may be related to the developmental alterations in pineal morphogenesis between the lower and higher vertebrate species. For developmental studies, avian embryos have great advantages for various experimental manipulations, such as cell and organ culture, surgical operation, and in situ transfection of developmental genes. The present review describes our cell culture studies, which have been done on developing rat and quail pineal organs, in order to elucidate the developmental potency of pineal cells and the regulatory mechanism involved in the phenotypic expression of cell properties. A number of phenotypes including numerous neuron-specific substances are shown immunohistochemically to be expressed only under culture conditions, and not observed in the mature pineal organ. As development proceeds, some of the potencies for cell differentiation are lost; hence, in the mature pineal organs most neuronal phenotypes are not expressed. Numerous factors were discovered which affect phenotypic expression of cultured pineal cells in a cell-type-specific manner. These findings, together with immunohistochemical observations on developing pineal organs, reveal that the developing pineal organ is a unique and useful model system for developmental neurobiology and that cell culture techniques offer a powerful tool for the understanding of development and cell differentiation of this particular organ.

Animals↗
PubMed2005

Methoxychlor disrupts uterine Hoxa10 gene expression.

Methoxychlor (MXC) is a pesticide that has adverse effects on reproductive capability in mice. MXC and its metabolites bind the estrogen receptor and function as endocrine disruptors. MXC diminishes the uterine decidual cell response, necessary for the support of pregnancy. Hoxa10 is an estrogen-regulated gene that is an essential mediator of the decidual response and necessary for pregnancy. Here we demonstrate that a mechanism by which MXC disrupts uterine function is by suppressing Hoxa10 expression. MXC treatment of mice produced a mild uterotropic response as measured by increased uterine weight and epithelial height. MXC treatment of uterine Ishikawa cells in vitro induced Hoxa10 expression. Estrogen receptor (ER) binding to the HOXA10 estrogen response element (ERE) was promoted by treatment with estradiol (E2); however, MXC disrupted E2/ER/ERE complex formation and gel shift. MXC alone allowed weak ER/ERE binding. In vivo MXC blocked the effect of E2 on Hoxa10 expression. Neonatal MXC treatment resulted in an immediate suppression and cellular restriction of Hoxa10 expression as well as a permanent generalized decrease in expression that persisted in the adult. MXC inhibited the expression of Hoxa10, a gene necessary for uterine development and function. One common mechanism by which endocrine disrupting chemicals produce lasting reproductive tract defects is through permanent alteration of developmental gene expression.

Animals↗
PubMed2003

Myoepithelial mRNA expression profiling reveals a common tumor-suppressor phenotype.

A series of myoepithelial cell lines and xenografts derived from benign human myoepithelial tumors of diverse sources (salivary gland, breast, and lung) exhibit common mRNA expression profiles indicative of a tumor-suppressor phenotype. Previously established myoepithelial cell lines and xenografts (HMS-#; HMS-#X) were compared to nonmyoepithelial breast carcinoma cells (MDA-MB-231 and MDA-MB-468, and inflammatory breast carcinoma samples, IBCr, and IBCw), a normal mammary epithelial cell line (HMEC) and individual cases of human breast cancer (zcBT#T), and matched normal human breast tissues (zcBT#N) (overall samples = 22). The global gene expression profile (22,000 genes) of these individual samples was examined using Affymetrix Microarray Gene Chips and subsequently analyzed with both Affymetrix and DChip algorithms. The myoepithelial cell lines/xenografts were distinct and very different from the nonmyoepithelial breast carcinoma cells and the normal breast and breast tumor biopsies. Two hundred and seven specifically selected genes represented a subset of genes that distinguished (P < 0.05) all the myoepithelial cell lines/xenografts from all the other samples and which themselves exhibited hierarchical clustering. Further analysis of these genes revealed increased expression in genes belonging to the classes of extracellular matrix proteins, angiogenic inhibitors, and proteinase inhibitors and decreased expression belonging to the classes of angiogenic factors and proteinases. Developmental genes were also differentially expressed (either over or underexpressed). These studies confirm our previous impression that human myoepithelial cells express a distinct tumor-suppressor phenotype.

Breast Neoplasms↗
PubMed2006

Automated cell lineage tracing in Caenorhabditis elegans.

The invariant cell lineage and cell fate of Caenorhabditis elegans provide a unique opportunity to decode the molecular mechanisms of animal development. To exploit this opportunity, we have developed a system for automated cell lineage tracing during C. elegans embryogenesis, based on 3D, time-lapse imaging and automated image analysis. Using ubiquitously expressed histone-GFP fusion protein to label cells/nuclei and a confocal microscope, the imaging protocol captures embryogenesis at high spatial (31 planes at 1 microm apart) and temporal (every minute) resolution without apparent effects on development. A set of image analysis algorithms then automatically recognizes cells at each time point, tracks cell movements, divisions and deaths over time and assigns cell identities based on the canonical naming scheme. Starting from the four-cell stage (or earlier), our software, named starrynite, can trace the lineage up to the 350-cell stage in 25 min on a desktop computer. The few errors of automated lineaging can then be corrected in a few hours with a graphic interface that allows easy navigation of the images and the reported lineage tree. The system can be used to characterize lineage phenotypes of genes and/or extended to determine gene expression patterns in a living embryo at the single-cell level. We envision that this automation will make it practical to systematically decipher the developmental genes and pathways encoded in the genome of C. elegans.

Animals↗
PubMed1990

Structural analyses of human developmentally regulated Vh3 genes.

In mice, a restricted set of the Jh-proximal Vh genes are preferentially expressed during early ontogeny. Recently, analyses of human Ig cDNA from a fetal liver revealed a restricted set of Vh genes which belong to the Vh1, 3, 4, and 6 families. Although the Vh6 and some Vh5 genes are proximal to the Jh region, no Vh5 gene was found in the fetal liver, suggesting that the distance between the Jh genes and some early-expressed Vh genes may not be the only factor responsible for Vh gene expression during early development. As an initial step in searching for other underlying mechanisms, we characterized two human germline Vh3 genes which belong to the developmentally restricted Vh repertoire, and found that they contain many enhancer-like sequences which are identical, or highly homologous to, various transcriptional enhancer motifs. Hence, it is conceivable that, in addition to the established positional effects, cis regulatory elements may be important in the programmed expression of some Vh genes during early B-lymphocyte development.

Base Sequence↗