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At least 235 records · Page 13Linked to original sources

PubMed2000

Human-mouse differences in the embryonic expression patterns of developmental control genes and disease genes.

Our understanding of early human development has been impeded by the general difficulty in obtaining suitable samples for study. As a result, and because of the extraordinarily high degree of evolutionary conservation of many developmentally important genes and developmental pathways, great reliance has been placed on extrapolation from animal models of development, principally the mouse. However, the strong evolutionary conservation of coding sequence for developmentally important genes does not necessarily mean that their expression patterns are as highly conserved. The very recent availability of human embryonic samples for gene expression studies has now permitted for the first time an assessment of the degree to which we can confidently extrapolate from studies of rodent gene expression patterns. We have found significant human-mouse differences in embryonic expression patterns for a variety of genes. We present detailed data for two illustrative examples. Wnt7a, a very highly conserved gene known to be important in early development, shows significant differences in spatial and temporal expression patterns in the developing brain (midbrain, telencephalon) of man and mice. CAPN3, the locus for LGMD2A limb girdle muscular dystrophy, and its mouse orthologue differ extensively in expression in embryonic heart, lens and smooth muscle. Our study also shows how molecular analyses, while providing explanations for the observed differences, can be important in providing insights into mammalian evolution.

5' Untranslated Regions↗

PubMed2002

Pem homeobox gene regulatory sequences that direct androgen-dependent developmentally regulated gene expression in different subregions of the epididymis.

The epididymis is a useful model system to understand the mechanisms that govern region-specific gene expression, as many gene products display spatially restricted expression within this organ. However, surprisingly little is known about how this regulation is achieved. Here, we report regulatory sequences from the Pem homeobox gene that drive expression in different subregions of the mouse epididymis in vivo. We found that the 0.3-kb 5'-flanking sequence (region I) from the Pem proximal promoter (Pem Pp) was sufficient to confer androgen-dependent and developmentally regulated expression in the caput region of the epididymis. Expression was restricted to the normal regions of expression of Pem in the caput (segments 2-4), but there was also aberrant expression in the corpus region. This corpus misexpression was extinguished when 0.6 kb of Pem Pp 5'-flanking sequence was included in the transgene, indicating that one or more negative regulatory elements exist between 0.6 and 0.3 kb upstream of the Pem Pp start site (region II). When heterologous sequences were introduced upstream of the Pem Pp, expression was further restricted, mainly to caput segment 3, implying that the Pem Pp has segment-specific regulatory elements. To our knowledge, the regulatory regions we have identified are the shortest so far defined that dictate regionally localized expression in the epididymis in vivo. They may be useful for identifying the factors that regulate region-specific expression in the epididymis, for expressing and conditionally knocking out genes in different subregions of the epididymis, for treating male infertility, and for generating novel methods of male contraception.

Androgens↗

PubMed1988

Activation of developmentally mutated human globin genes by cell fusion.

Human fetal globin genes are not expressed in hybrid cells produced by the fusion of normal human lymphocytes with mouse erythroleukemia cells. In contrast, when lymphocytes from persons with globin gene developmental mutations (hereditary persistence of fetal hemoglobin) are used for these fusions, fetal globin is expressed in the hybrid cells. Thus, mutations of developmental origin can be reconstituted in vitro by fusing mutant lymphoid cells with differentiated cell lines of the proper lineage. This system can readily be used for analyses, such as globin gene methylation, that normally require large numbers of pure nucleated erythroid cells, which are difficult to obtain.

Animals↗

PubMed2001

Gene-selective developmental roles of general transcription factors.

Innumerable transcription factors integrate cellular and intercellular signals to generate a profile of expressed genes that is characteristic of the biochemical and cellular properties of the cell. This profile of expressed genes changes dynamically along with the developmental stage and differentiation state of the cell. The biochemical machinery upon which transcription factors integrate their signals is referred to as the general transcription machinery. However, this machinery is not of universal composition, and variants of the general transcription factors play specific roles in embryonic development, reflecting the constraints and requirements of developmental gene regulation.

Animals↗

PubMed1988

Characterization of an unusual cAMP receptor and its related polypeptides in Dictyostelium discoideum.

Several lines of evidence indicate that cAMP modulates developmental gene activity via cell-surface receptors. We describe here a novel cAMP receptor, CABP1, whose properties are consistent with the idea that this protein is involved in gene regulation. Firstly, immunological techniques using anti-CABP1 antibodies as probes showed that this cAMP receptor can be detected on the surface of developing cells. Secondly, there is a steady migration of CABP1 to the nucleus during development. Thirdly, some genetic variants exhibiting an altered pattern of development are found to possess modified CABP1. We also showed that CABP1 co-purifies with at least seven other polypeptides which share common epitopes with CABP1. Interestingly, four of the CABP1-related polypeptides can be detected on the cell surface as well as in the nucleus.

Dictyostelium↗

PubMed1987

Relationships between cell-cell interactions, cAMP, and gene expression in a developmental mutant of Dictyostelium discoideum.

Previous work has led us to propose that close cell-cell associations during D. discoideum development serve as a signal to deactivate expression of discoidin I mRNA, and that intracellular cAMP serves as a mediator of this regulatory pathway. This model is based in part on the failure of a morphogenetic mutant, EB-21, to deactivate discoidin I expression under conditions where these cells fail to acquire cell-cell cohesiveness and hence remain as single cells, unlike the wild type strain which forms multicellular aggregates. Here we show that the failure of EB-21 to express specific cohesiveness depends on developmental conditions, and that under conditions where close cell-cell associations are allowed to form, discoidin I mRNA expression is deactivated normally. Furthermore, in both wild type and EB-21 there is a close correlation between formation close cell-cell associations and elevation of intracellular cAMP under different developmental conditions. Additional analyses of the biological behavior of EB-21 indicate that it acquires a normal cAMP chemotactic signal-response system, and that the morphogenetic defect cannot be corrected by co-development with wild type cells. The results are discussed in terms of possible relationships between cell-cell interactions, cAMP metabolism, and developmental gene expression in this organism.

Chemotaxis↗

PubMed1994

Tumor suppressor and overgrowth suppressor genes of Drosophila melanogaster: developmental aspects.

In Drosophila about 27 developmental genes have been identified which suppress tumorous growth and about as many genes are known to suppress overgrowth. Recessive lethal mutations in tumor suppressor genes block in one step the differentiation of specific target cells, leaving unaffected their capacity to divide in an autonomous, malignant and lethal fashion. The structural analysis of eight tumor suppressor genes predicts putative functions in differentiation events, such as cell-cell communication, protein transport and protein synthesis, signal transduction, sex determination splicing and cytokinesis. Their predicted products function as effectors of the differentiated state being vital components of cell junctions, the cytoskeleton, the protein synthetic apparatus, the splicing machinery and signal transduction. In contrast to the tumor suppressor genes, which are instrumental in the establishment and maintenance of the differentiated state, overgrowth suppressor genes seem to control cell-specific division rates while leaving unaffected the capacity of the cells to differentiate. The Drosophila tumor suppressor and overgrowth suppressor genes show clearly the mutual exclusion of the genetic programs controlling cell division and cell differentiation. Some of the genes exhibit homologies to mammalian genes. Their functional homology, however, is still an open question.

Animals↗

PubMed2003

Morpholino-based gene knockdown screen of novel genes with developmental function in Ciona intestinalis.

In the present study, we conducted an extensive analysis to identify novel genes with developmental function among Ciona intestinalis genes discovered by cDNA projects. Translation of a total of 200 genes expressed during embryogenesis was suppressed by using specific morpholino antisense oligonucleotides. Suppression of the translation of any of 40 genes (one-fifth of the genes tested) was thereby shown to cause specific embryonic defects. Most of these genes have counterpart(s) in mouse and human, suggesting that the present approach will be useful for identifying candidate genes essential for the development of vertebrates. Suppression of translation of 14 of these 40 genes resulted in the 'disorganized body plan' phenotype characterized by gross morphological abnormalities caused by early defects in embryogenesis. These genes encode zinc-finger, transmembrane or Pbx homeodomain proteins. The morphological features of larvae of this phenotypic class varied according to the gene suppressed, suggesting that a distinct developmental event such as tissue specification or cell cycle progression was affected in each type of larva. Suppression of the remaining 26 genes resulted in the 'abnormal tail' phenotype. Some of these genes encode proteins with known functional structures such as Zn-finger and HLH motifs. Twelve genes among them are especially interesting, because their suppression produced defects in the nervous system, as demonstrated by the loss of the sensory pigment cells or palps of the adhesive organ in the knockdown larvae. These results suggest that screening for developmental genes by the reverse genetic approach in Ciona intestinalis embryos is effective for identifying novel genes with developmental functions required for the development of chordates.

Animals↗

PubMed1999

A developmentally regulated gene cluster involved in conidial pigment biosynthesis in Aspergillus fumigatus.

Aspergillus fumigatus, a filamentous fungus producing bluish-green conidia, is an important opportunistic pathogen that primarily affects immunocompromised patients. Conidial pigmentation of A. fumigatus significantly influences its virulence in a murine model. In the present study, six genes, forming a gene cluster spanning 19 kb, were identified as involved in conidial pigment biosynthesis in A. fumigatus. Northern blot analyses showed the six genes to be developmentally regulated and expressed during conidiation. The gene products of alb1 (for "albino 1"), arp1 (for "aspergillus reddish-pink 1"), and arp2 have high similarity to polyketide synthases, scytalone dehydratases, and hydroxynaphthalene reductases, respectively, found in the dihydroxynaphthalene (DHN)-melanin pathway of brown and black fungi. The abr1 gene (for "aspergillus brown 1") encodes a putative protein possessing two signatures of multicopper oxidases. The abr2 gene product has homology to the laccase encoded by the yA gene of Aspergillus nidulans. The function of ayg1 (for "aspergillus yellowish-green 1") remains unknown. Involvement of the six genes in conidial pigmentation was confirmed by the altered conidial color phenotypes that resulted from disruption of each gene in A. fumigatus. The presence of a DHN-melanin pathway in A. fumigatus was supported by the accumulation of scytalone and flaviolin in the arp1 deletant, whereas only flaviolin was accumulated in the arp2 deletants. Scytalone and flaviolin are well-known signature metabolites of the DHN-melanin pathway. Based on DNA sequence similarity, gene disruption results, and biochemical analyses, we conclude that the 19-kb DNA fragment contains a six-gene cluster which is required for conidial pigment biosynthesis in A. fumigatus. However, the presence of abr1, abr2, and ayg1 in addition to alb1, arp1, and arp2 suggests that conidial pigment biosynthesis in A. fumigatus is more complex than the known DHN-melanin pathway.

Amino Acid Sequence↗

PubMed1999

Psychiatric disorder and cognitive function in a family with an inherited novel mutation of the developmental control gene PAX6.

The PAX family of developmental control genes are known to play important roles in the early patterning of the central nervous system. One member of this family, PAX6, is involved in eye development in invertebrates as well as in mouse and man, but is also widely expressed in the developing forebrain. Humans with a mutation in this gene have abnormalities of eye development, and the results presented here suggest, for the first time, that this mutation may also be associated with subtle abnormalities of frontal lobe function in the family studied. We carried out genotyping of individuals within a single family, with and without the characteristic eye abnormalities of PAX6 mutation, and only those individuals with the mutation showed significant abnormalities on tests of frontal lobe function. These individuals also had higher rates of psychiatric disorder. PAX6 is highly conserved between mouse and man, and although the neuroanatomical phenotype associated with PAX6 heterozygosity has only been studied in mice, the resultant cellular disorganization seen in mice is likely to be present in the human forebrain. Although these mice have no obvious behavioural phenotype, the results presented here suggest that humans with the equivalent mutation display a neurobehavioural phenotype.

Adolescent↗

PubMed2000

Recovery of developmentally defined gene sets from high-density cDNA macroarrays.

New technologies for isolating differentially expressed genes from large arrayed cDNA libraries are reported. These methods can be used to identify genes that lie downstream of developmentally important transcription factors and genes that are expressed in specific tissues, processes, or stages of embryonic development. Though developed for the study of gene expression during the early embryogenesis of the sea urchin Strongylocentrotus purpuratus, these technologies can be applied generally. Hybridization parameters were determined for the reaction of complex cDNA probes to cDNA libraries carried on six nylon filters, each containing duplicate spots from 18,432 bacterial clones (macroarrays). These libraries are of sufficient size to include nearly all genes expressed in the embryo. The screening strategy we have devised is designed to overcome inherent sensitivity limitations of macroarray hybridization and thus to isolate differentially expressed genes that are represented only by low-prevalence mRNAs. To this end, we have developed improved methods for the amplification of cDNA from small amounts of tissue (as little as approximately 300 sea urchin embryos, or 2 x 10(5) cells, or about 10 ng of mRNA) and for the differential enhancement of probe sequence concentration by subtractive hybridization. Quantitative analysis of macroarray hybridization shows that these probes now suffice for detection of differentially expressed mRNAs down to a level below five molecules per average embryo cell.

Animals↗

PubMed2005

HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL).

Using a combination of molecular cytogenetic and large-scale expression analysis in human T-cell acute lymphoblastic leukemias (T-ALLs), we identified and characterized a new recurrent chromosomal translocation, targeting the major homeobox gene cluster HOXA and the TCRB locus. Real-time quantitative polymerase chain reaction (RQ-PCR) analysis showed that the expression of the whole HOXA gene cluster was dramatically dysregulated in the HOXA-rearranged cases, and also in MLL and CALM-AF10-related T-ALL cases, strongly suggesting that HOXA genes are oncogenic in these leukemias. Inclusion of HOXA-translocated cases in a general molecular portrait of 92 T-ALLs based on large-scale expression analysis shows that this rearrangement defines a new homogeneous subgroup, which shares common biologic networks with the TLX1- and TLX3-related cases. Because T-ALLs derive from T-cell progenitors, expression profiles of the distinct T-ALL subgroups were analyzed with respect to those of normal human thymic subpopulations. Inappropriate use or perturbation of specific molecular networks involved in thymic differentiation was detected. Moreover, we found a significant association between T-ALL oncogenic subgroups and ectopic expression of a limited set of genes, including several developmental genes, namely HOXA, TLX1, TLX3, NKX3-1, SIX6, and TFAP2C. These data strongly support the view that the abnormal expression of developmental genes, including the prototypical homeobox genes HOXA, is critical in T-ALL oncogenesis.

Adolescent↗

PubMed2002

Toxoplasma gondii asexual development: identification of developmentally regulated genes and distinct patterns of gene expression.

Asexual development in Toxoplasma gondii is a vital aspect of the parasite's life cycle, allowing transmission and avoidance of the host immune response. Differentiation of rapidly dividing tachyzoites into slowly growing, encysted bradyzoites involves significant changes in both physiology and morphology. We generated microarrays of approximately 4,400 Toxoplasma cDNAs, representing a minimum of approximately 600 genes (based on partial sequencing), and used these microarrays to study changes in transcript levels during tachyzoite-to-bradyzoite differentiation. This approach has allowed us to (i) determine expression profiles of previously described developmentally regulated genes, (ii) identify novel developmentally regulated genes, and (iii) identify distinct classes of genes based on the timing and magnitude of changes in transcript levels. Whereas microarray analysis typically involves comparisons of mRNA levels at different time points, we have developed a method to measure relative transcript abundance between genes at a given time point. This method was used to determine transcript levels in parasites prior to differentiation and to further classify bradyzoite-induced genes, thus allowing a more comprehensive view of changes in gene expression than is provided by standard expression profiles. Newly identified developmentally regulated genes include putative surface proteins (a SAG1-related protein, SRS9, and a mucin-domain containing protein), regulatory and metabolic enzymes (methionine aminopeptidase, oligopeptidase, aminotransferase, and glucose-6-phosphate dehydrogenase homologues), and a subset of genes encoding secretory organelle proteins (MIC1, ROP1, ROP2, ROP4, GRA1, GRA5, and GRA8). This analysis permits the first in-depth look at changes in gene expression during development of this complex protozoan parasite.

Animals↗

PubMed1992

Dominant mutation of the murine Hox-2.2 gene results in developmental abnormalities.

Genes carrying the homeobox were originally identified in Drosophila, in which they are now known to play key roles in establishing segmentation patterns and in determining segment identities. A number of genes with striking homology to the Drosophila homeobox genes have now been found in the mouse genome, and mutational analysis is beginning to shed light on their function in mammalian development. To understand better the developmental significance of the murine Hox-2.2 gene, we have generated gain of function mutants by using the chicken beta-actin promoter to drive ubiquitous expression in transgenic mice. The resulting Hox-2.2 misexpression produces early postnatal lethality as well as craniofacial and axial skeletal perturbations that include open eyes at birth, cleft palate, micrognathia, microtia, skull bone deficiencies, and structural and positional alterations in the vertebral column. We repeatedly observe complete or partial absence of the supraoccipital bone and malformations of the exoccipital and the basioccipital bones. These results suggests a role for the Hox-2.2 gene in specifying positional identity along the anterior-posterior axis.

Abnormalities, Multiple↗

PubMed2006

Transcript profiles of some developmentally important genes detected in bovine oocytes and in vitro-produced blastocysts using RNA amplification and cDNA microarrays.

To study the mRNA transcript profiles of some potential candidate developmental genes during bovine oocyte and blastocyst stages, RNA amplification procedures, cDNA microarray of 82 target genes spotted onto glass slide and real-time polymerase chain reaction (PCR) were used. Messenger RNAs were isolated from in vitro-produced bovine matured oocytes and blastocysts. Using equal amounts of input mRNAs but different cycles of amplifications, cDNAs were produced and served as template for RNA amplification by the in vitro transcriptions. After amplification, the RNA yields transcribed from cDNAs of different cycles were evaluated both by hybridization on the cDNA microarrays and by using real-time PCR techniques. The analyses indicated best results from lower amplification cycle templates with consistent signals at hybridization. Generally, the RNA yield was directly proportional to the amplification cycle but inversely related with signal consistency at repeated hybridizations. Using the protocols established, equal amounts of amplified RNA from matured oocytes and blastocysts were hybridized to the array. Analyses of replicated hybridizations indicated that 35 transcripts were differentially expressed. Most of these were not described in previous bovine embryo studies. Independent analyses of 23 transcripts with real-time PCR and unamplified RNA confirmed the results of 22 genes. Moreover, the functional analyses showed various roles related to development. Hence, it is possible to conclude that the genes identified here are potential candidates for characterizing developmental competence, and that the methods established can be used for large-scale gene expression analysis with more comprehensive arrays.

Animals↗

PubMed1995

Identification of developmental regulatory genes in Aspergillus nidulans by overexpression.

Overexpression of several Aspergillus nidulans developmental regulatory genes has been shown to cause growth inhibition and development at inappropriate times. We set out to identify previously unknown developmental regulators by constructing a nutritionally inducible A. nidulans expression library containing small, random genomic DNA fragments inserted next to the alcA promoter [alcA(p)] in an A. nidulans transformation vector. Among 20,000 transformants containing random alcA(p) genomic DNA fusion constructs, we identified 66 distinct mutant strains in which alcA(p) induction resulted in growth inhibition as well as causing other detectable phenotypic changes. These growth inhibited mutants were divided into 52 FIG (Forced expression Inhibition of Growth) and 14 FAB (Forced expression Activation of brlA) mutants based on whether or not alcA(p) induction resulted in accumulation of mRNA for the developmental regulatory gene brlA. In four FAB mutants, alcA(p) induction not only activated brlA expression but also caused hyphae to differentiate into reduced conidiophores that produced viable spores from the tips as is observed after alcA(p)::brlA induction. Sequence analyses of the DNA fragments under alcA(p) control in three of these four sporulating strains showed that in two cases developmental activation resulted from overexpression of previously uncharacterized genes, whereas in the third strain, the alcA(p) was fused to brlA. The potential uses for this strategy in identifying genes whose overexpression results in specific phenotypic changes like developmental induction are discussed.

Alcohol Dehydrogenase↗

PubMed1984

Molecular analysis of a developmentally regulated gene which is expressed in the larval salivary gland of Drosophila.

The polytene genome of the larval salivary gland of Drosophila undergoes dramatic alterations in localized transcriptional activity late in third-instar development. One of these changes involves the 20-OH ecdysone-mediated and coordinate repression of a dispersed set of intermolt puff sites. The DNA from one of these loci (that located within the 90BC interval) has been isolated by molecular cloning techniques. This DNA was shown to be present one time per haploid Drosophila genome and to contain a gene (designated the Group V gene) which is developmentally regulated. The Group V transcript was shown to accumulate only during third-instar larval development and to be located exclusively in the salivary gland. These results are consistent with the hypothesis that the Group V gene codes for a salivary gland glue protein.

Animals↗

PubMed1991

Response to heat shock of gene 1, a Drosophila melanogaster small heat shock gene, is developmentally regulated.

The expression of gene 1, a member of the small heat shock gene family from the Drosophila melanogaster chromosomal locus 67B was studied. In contrast to the other heat shock genes, the response of gene 1 to stress was modulated during development. In the absence of stress, gene 1 was expressed at the beginning of pupation, and at a very low level in adult males. Expression of gene 1 was substantially increased by heat shock in pupae, but was one to two orders of magnitude lower in adults or in embryos. Under the same conditions, hsp70 or hsp26 were induced to similar levels in all stages. This developmental effect could be mimicked in cultured Drosophila cells: expression of gene 1 was stimulated by heat shock in the presence, but not in the absence, of the moulting hormone ecdysterone, while the level of expression of hsp26 and hsp70 in response to heat shock was independent of the presence of the hormone. Thus, the presence and activity of the heat shock transcription factor are not sufficient for the maximal response of gene 1 to stress. These results suggest that the heat shock activator protein requires additional factors, which are developmentally regulated, to activate transcription of gene 1. Furthermore, S1 nuclease mapping analysis revealed several gene 1 mRNA species, which are generated by the use of alternative polyadenylation sites and by the use of differentially regulated transcriptional initiation sites.

Animals↗