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PubMed1999

Genotoxicity and diabetic embryopathy: impaired expression of developmental control genes as a cause of defective morphogenesis.

Since the advent of insulin therapy for diabetes mellitus, the survival of mothers with diabetes prior to pregnancy and their offspring has greatly improved. Nevertheless, the observation that the earliest stages of organogenesis can be impaired in the offspring of women with diabetes raises the question of how abnormal fuel metabolism disturbs embryogenesis. Research into this process has been made possible in recent years by advances in molecular biology which makes it possible to study gene expression in early embryos, and by the availability of genetically engineered mutant mouse strains. Using these approaches, a model is emerging in which elevated glucose, by disturbing expression of genes which regulate embryonic development and cell cycle progression, causes premature cell death of emerging organ structures, thereby causing defective morphogenesis. Investigation into the signaling mechanisms by which excess glucose metabolism exhibits toxic effects on embryo gene expression will explain how diabetic embryopathy occurs on a molecular and cellular level, as well as increase our understanding of the role of metabolic homeostasis in proper embryonic development.

Animals↗
PubMed1991

Segmentation gene expression in the housefly Musca domestica.

Drosophila and Musca both belong to the group of higher dipteran flies and show morphologically a very similar early development. However, these two species are evolutionary separated by at least 100 million years. This presents the opportunity for a comparative analysis of segmentation gene expression across a large evolutionary distance in a very similar embryonic background. We have analysed in detail the early expression of the maternal gene bicoid, the gap genes hunchback, Krüppel, knirps and tailless, the pair-rule gene hairy, the segment-polarity gene engrailed and the homoeotic gene Ultrabithorax. We show that the primary expression domains of these genes are conserved, while some secondary expression aspects have diverged. Most notable is the finding of hunchback expression in 11-13 stripes shortly before gastrulation, as well as a delayed expression of terminal domains of various genes. We conclude that the early developmental gene hierarchy, as it has been defined in Drosophila, is evolutionary conserved in Musca domestica.

Animals↗
PubMed1996

Developmentally regulated gene expression of thrombomodulin in postimplantation mouse embryos.

Embryonic lethality of thrombomodulin-deficient mice has indicated an essential role for this regulator of blood coagulation in murine development. Here, the embryonic expression pattern of thrombomodulin was defined by surveying beta-galactosidase activity in a mouse strain in which the reporter gene was placed under the regulatory control of the endogenous thrombomodulin promoter via homologous recombination in embryonic stem cells. The murine trophoblast was identified as a previously unrecognized anatomical site where TM expression is conserved between humans and mice and may exert a critical function during postimplantation development. Targeted reporter gene expression in mesodermal precursors of the endothelial cell lineage defined thrombomodulin as an early marker of vascular differentiation. Analysis of the thrombomodulin promoter in differentiating ES cells and in transgenic mice provided evidence for a disparate and cell type-specific gene regulatory control mechanism in the parietal yolk sac. The thrombomodulin promoter as defined in this study will allow the targeting of gene expression to the parietal yolk sac of transgenic mice and the initiation of investigations into the role of parietal endoderm in placental function.

Animals↗
PubMed2000

Chromatin fine structure profiles for a developmentally regulated gene: reorganization of the lysozyme locus before trans-activator binding and gene expression.

The chicken lysozyme locus is activated in a stepwise fashion during myeloid differentiation. We have used this locus as a model to study at high resolution changes in chromatin structure both in chicken cell lines representing various stages of macrophage differentiation and in primary cells from transgenic mice. In this study we have addressed the question of whether chromatin rearrangements can be detected in myeloid precursor cells at a stage well before overt transcription of the lysozyme gene begins. In addition to restriction enzyme accessibility assays and DMS footprinting, we have applied new, very sensitive techniques to assay for chromatin changes. Particularly informative was UV photofootprinting, using terminal transferase-dependent PCR and nonradioactive detection. We find that the basic chromatin structure in lysozyme nonexpressing hematopoietic precursor cells is highly similar to the pattern found in fully differentiated lysozyme-expressing cells. In addition, we find that only in nonexpressing cells are dimethylsulfate footprints and UV photofootprints affected by trichostatin, an inhibitor of histone deacetylation. These results are interpreted to mean that most chromatin pattern formation is complete before the binding of end-stage trans-activators, supporting the notion that heritable chromatin structure is central to the stable epigenetic programs that guide development.

Animals↗
PubMed1994

The human alpha 2 integrin gene promoter. Identification of positive and negative regulatory elements important for cell-type and developmentally restricted gene expression.

The alpha 2 beta 1 serves as a collagen receptor or a collagen/laminin receptor, depending upon cell type. Expression of the integrin is regulated during normal cellular differentiation and is altered during carcinogenesis. We have previously demonstrated that increased expression of the alpha 2 beta 1 integrin during megakaryocytic differentiation is a consequence of increased alpha 2 mRNA due to transcriptional activation of the alpha 2 integrin gene and that the decreased expression of the integrin in breast adenocarcinoma is due to decreased steady-state levels of alpha 2 mRNA. We now report the identification and characterization of the 5'-flanking region of the alpha 2 integrin gene. The 5'-untranslated region of the alpha 2 mRNA extends 129 base pairs 5' to the site of translation initiation. The promoter region lacks TATA and CAAT boxes but contains an abbreviated initiator sequence and six Sp1 binding sites. Consensus binding sites for AP-1 and AP-2 complexes, a GATA box, a Pu.1 box, and two palindromic motifs with potential to bind the estrogen receptor are also present. A 961-base pair fragment of the 5'-flanking region directs both cell type- and differentiation-specific expression of a reporter gene in T47-D epithelial cells and in pluripotent hematopoietic K562 cells upon megakaryocytic differentiation.

Amino Acid Sequence↗
PubMed2003

A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain.

Approximately 3-10% of people have specific difficulties in reading, despite adequate intelligence, education, and social environment. We report here the characterization of a gene, DYX1C1 near the DYX1 locus in chromosome 15q21, that is disrupted by a translocation t(2;15)(q11;q21) segregating coincidentally with dyslexia. Two sequence changes in DYX1C1, one involving the translation initiation sequence and an Elk-1 transcription factor binding site (-3G --> A) and a codon (1249G --> T), introducing a premature stop codon and truncating the predicted protein by 4 aa, associate alone and in combination with dyslexia. DYX1C1 encodes a 420-aa protein with three tetratricopeptide repeat (TPR) domains, thought to be protein interaction modules, but otherwise with no homology to known proteins. The mouse Dyx1c1 protein is 78% identical to the human protein, and the nonhuman primates differ at 0.5-1.4% of residues. DYX1C1 is expressed in several tissues, including the brain, and the protein resides in the nucleus. In human brain, DYX1C1 protein localizes to a fraction of cortical neurons and white matter glial cells. We conclude that DYX1C1 should be regarded as a candidate gene for developmental dyslexia. Detailed study of its function may open a path to understanding a complex process of development and maturation of the human brain.

Base Sequence↗
PubMedDate not supplied

Transforming growth factor-beta 1 regulates the expression of Pax-2, a developmental control gene, in renal tubule cells.

BACKGROUND/AIMS: The pattern-forming event of kidney tubulogenesis is initiated by the inductive transition of mesenchymal cells to epithelial phenotype; a transition that is critically dependent on the regulated expression of the developmental control gene, Pax-2. Because of a defined role in in vitro renal tubulogenesis, the effects of epidermal growth factor (EGF), transforming growth factor (TGF)-beta 1 and retinoic acid on Pax-2 gene expression in proximal tubule cells (PTC) were evaluated. METHODS: Rabbit PTC were isolated and grown in tissue culture. Under confluent quiescent conditions, the effect of various factors on Pax-2 gene expression was assessed by Northern blot analysis. To assess whether the effect of TGF-beta 1 to alter Pax-2 gene expression was due to transcriptional or posttranscriptional events, nuclear run-on assays were also undertaken. RESULTS: Under control, confluent growth conditions, PTC expressed high levels of Pax-2. A 24-hour exposure to EGF (10 nM), a potent mitogen of PTC, increased this level of expression. In contrast, Pax-2 gene expression was suppressed by treating PTC with retinoic acid (10 mM), a well-described differentiating factor, and with TGF-beta 1 (10 ng/ml), a recognized antiproliferative agent for these cells, which suggests that Pax-2 has a role in renal cell proliferation. The mechanism of the effect of TGF-beta 1 on Pax-2 mRNA levels was further detailed. TGF-beta 1 did not affect Pax-2 transcription rates, as assessed by nuclear run-on assays; however, in a dose-dependent manner, it diminished the stability of Pax-2 mRNA. At a concentration of 10 ng/ml, TGF-beta 1 reduced Pax-2 mRNA stability from a control half-life of 120 min to a half-life of less than 60 min. CONCLUSION: This study demonstrates that various soluble inductive factors affect Pax-2 gene expression in renal tubule cells. Also, TGF-beta 1 downregulates Pax-2 gene expression through a posttranscriptional process, an acknowledged mechanism for modulating important growth regulatory gene products.

Animals↗
PubMed1999

Use of developmental marker genes to define temporal and spatial patterns of differentiation during embryoid body formation.

Mouse embryonic stem cells are pluripotent cells that are derived from the inner cell mass of blastocysts. When induced to synchronously enter a program of differentiation in vitro, they form embryoid bodies that contain cells of the mesodermal, hematopoietic, endothelial, muscle, and neuronal lineages. Here, we used a panel of marker genes with early expression within the germ layers (oct-3, Brachyury T, Fgf-5, nodal, and GATA-4) or a variety of lineages (flk-1, Nkx-2.5, EKLF, and Msx3) to determine how progressive differentiation of embryoid bodies in culture correlated with early postimplantation development of mouse embryos. Using RNA in situ hybridization, we found that the temporal and spatial relationships existing between these marker genes in vivo were maintained also in vitro. Studying the onset of marker gene expression allowed us also to determine the time course of differentiation during the formation of embryoid bodies. Thus, stages equivalent to embryogenesis between implantation and the beginning of gastrulation (4.5-6.5 d.p.c.) occur within the first two days of embryoid body differentiation. Between days 3 and 5, embryoid bodies contain cell lineages found in embryos during gastrulation at 6.5 to 7.0 d.p.c., and after day 6 in culture, embryoid bodies are equivalent to early organogenesis-stage embryos (7.5 d.p.c.). In addition, we demonstrate that the panel of developmental markers can be applied in a screen for stage- or lineage-specific genes. Reporter gene expression from entrapment vector insertions can be co-localized with expression of specific markers within the same cell during embryoid body formation as well as during embryogenesis. Our results thus demonstrate the power of embryoid body formation as an in vitro model system to study early lineage determination and organogenesis in mammals, and indicate that they will prove to be useful tools for identifying developmental genes whose expression is restricted to particular lineages.

Animals↗
PubMed1994

H19, a developmentally regulated gene, is reexpressed in rat vascular smooth muscle cells after injury.

Vascular smooth muscle cell migration, proliferation, and differentiation are central to blood vessel development. Since neointimal formation after vascular injury may require the reexpression of a smooth muscle developmental sequence, we examined the expression of H19, a developmentally regulated gene, in rat blood vessels. Expression of the H19 gene is associated with the differentiation process that takes place during development of many tissues. Consistent with this, H19 was highly expressed in the 1-d-old rat aorta but was undetectable in the adult. H19 transcripts were only minimally detected in uninjured carotid artery but were abundant at 7 and 14 d after injury and were localized by in situ hybridization, primarily to the neointima. H19 transcript were undetectable in proliferating neointimal cells in culture but became highly abundant in postconfluent, differentiated neointimal cells. H19 transcripts were only minimally expressed in adult medial smooth muscle cells grown under the identical conditions. Thus, H19 may play an important role in the normal development and differentiation of the blood vessel and in the phenotypic changes of the smooth muscle cells, which are associated with neointimal lesion formation. The vascular injury model may be a useful system to use in examining the function of H19.

Aging↗
PubMed1991

Spectrum of heart malformations in mice with situs solitus, situs inversus, and associated visceral heterotaxy.

BACKGROUND: We present a study of the heart malformations found in a collection of mouse fetuses of the iv/iv strain between days 16.5 and 18.5 of gestation. METHODS AND RESULTS: One hundred hearts were serially sectioned and studied by segmental analysis with a light microscope. Forty additional hearts were analyzed with a scanning microscope. Forty percent of the hearts were found to be malformed. The most frequently occurring heart malformations were persistence of the sinus venosus (9%), common atrium (17%), common atrioventricular canal (24%), double-outlet right ventricle (12%), Fallot's tetralogy (8%), and transposition of the great arteries (5%). These malformations do not usually occur in isolation but rather appear in the formation of complex cardiopathies. The most severe and frequent is the combination of persistence of sinus venosus, common atrium, common atrioventricular canal, and double-outlet right ventricle; this is the "bulboventricular heart." The morphology of each lesion, as well as the degree of association, is similar to that found in human hearts with complex cardiopathies. Some of these cardiopathies appear to be directly related to formation of the cardiac loop. The iv/iv mouse appears to constitute an excellent model with which to study the etiology and pathogenesis of complex heart defects in humans. These hearts show a high phenotypic variability in the presentation of heart lesions. From a genetic viewpoint, there is a basic defect--the bulboventricular heart--which can be considered congenital. The other malformations can be considered formes frustes of the defect type. CONCLUSIONS: The iv gene is a developmental gene that affects basic developmental mechanisms. In this regard, heart lesions may not be the primary result of the abnormal gene activity but rather are secondary to defective interactions during cardiac development.

Animals↗
PubMed2005

Expression patterns of three heat shock protein 70 genes among developmental stages of the red flour beetle, Tribolium castaneum (Coleoptera: Tenebrionidae).

Three genes were identified encoding heat shock protein 70's in Tribolium castaneum (Herbst) and they were tentatively named as tchsp70 I, tchsc70 II, and tchsp70 III. Comparison of deduced amino acid sequences of tchsp70 I and tchsc70 II showed 99% identity. However, the amino acid sequence of tchsp70 III was only 58.5% identical to those of tchsp70 I and tchsc70 II. Stage-specific expression patterns of the tchsp70 were investigated in young larvae, old larvae, pupae, and adults of T. castaneum exposed for 1 h to 23 degrees C (control) or 40 degrees C (heat-shock). Northern blot and real-time quantitative PCR analyses were carried out to determine mRNA levels in each life stage. Transcripts of all three genes were detected by Northern blotting, and the sizes were 2.4- 2.2-, and 2.3-kb for tchsp70 I, tchsc70 II, and tchsp70 III, respectively. A 1.1- to 2.0-fold increased expression of tchsp70 I mRNA was found in heat-shocked developmental stages compared with the control. The expression of tchsc70 II mRNA among developmental stages was similar between heat-shocked and control insects, and the expression of tchsp70 III mRNA varied among developmental stages. Results suggest that the expression of tchsp70 I gene is heat-inducible, tchsc70 II is constitutive, and tchsp70 III is developmentally regulated in T. castaneum.

Amino Acid Sequence↗
PubMed1997

Methods to prepare RNA and to isolate developmentally regulated genes from Eimeria.

Coccidians represent a large class of important intracellular parasites that traverse multiple developmental stages that are distinct and required to complete the life cycle. The biochemical details underlying the regulation of transformation from one developmental form to the next are limited and the study of such details presents unique obstacles. However, the genetic program is critical and may provide a basis for understanding the biology of these organisms in addition to the opportunity to suppress development and infection. We provide a basic overview of several strategies, including previously unpublished results, used by this laboratory to isolate stage-specific genes from Eimeria bovis. Additionally, we have included detailed discussions that summarize the associated advantages and disadvantages of each as applied to coccidia and potentially to other parasites in the phylum Apicomplexa. Given that the purification of sufficient quantities of high-quality RNA is vital, we have included detailed protocols for the isolation of RNA from various parasite stages. Also included is a detailed protocol to apply mRNA differential display to investigate stage-specific developmental regulation.

Animals↗
PubMed2002

Genetic analysis of tachyzoite to bradyzoite differentiation mutants in Toxoplasma gondii reveals a hierarchy of gene induction.

Developmental switching in Toxoplasma gondii, from the virulent tachyzoite to the relatively quiescent bradyzoite stage, is responsible for disease propagation and reactivation. We have generated tachyzoite to bradyzoite differentiation (Tbd-) mutants in T. gondii and used these in combination with a cDNA microarray to identify developmental pathways in bradyzoite formation. Four independently generated Tbd- mutants were analysed and had defects in bradyzoite development in response to multiple bradyzoite-inducing conditions, a stable phenotype after in vivo passages and a markedly reduced brain cyst burden in a murine model of chronic infection. Transcriptional profiles of mutant and wild-type parasites, growing under bradyzoite conditions, revealed a hierarchy of developmentally regulated genes, including many bradyzoite-induced genes whose transcripts were reduced in all mutants. A set of non-developmentally regulated genes whose transcripts were less abundant in Tbd- mutants were also identified. These may represent genes that mediate downstream effects and/or whose expression is dependent on the same transcription factors as the bradyzoite-induced set. Using these data, we have generated a model of transcription regulation during bradyzoite development in T. gondii. Our approach shows the utility of this system as a model to study developmental biology in single-celled eukaryotes including protozoa and fungi.

Animals↗
PubMed1998

Sp1 as a target site for metal-induced perturbations of transcriptional regulation of developmental brain gene expression.

Differential gene expression is partially regulated by zinc finger proteins (ZFP) such as Sp1, which may be potential targets for perturbations by environmental metals. In this paper, we discuss the selective effects of lead (Pb) and other heavy metals on the in vitro and in vivo DNA-binding of Sp1, and the developmental expression of its target genes. We have found that the presence of Pb, Zn and Cd in a DNA-binding assay differentially modulated the binding of Sp1 to its specific DNA sequence, while Ca, Mg and Ba, did not. In PC12 cells, cultured in the presence of low concentrations of Pb, a premature enhancement of Sp1 DNA-binding was observed. Similarly, Sp1 DNA-binding in the cerebellum of Pb-exposed animals was shifted to the first week after birth, while the developmental profile of a non-ZFP, NFkB, was not. Furthermore, selective premature peaks of myelin basic protein and proteolipid protein mRNA expression were observed to occur in a manner relative to the changes in Sp1 DNA-binding. Since these genes are high targets for Sp1, these data suggest that exposure to heavy metals may alter developmental gene expression and brain development through selective modulation of the transcriptional activity of Sp1.

Animals↗
PubMed2000

Involvement of the period gene in developmental time-memory: effect of the perShort mutation on phase shifts induced by light pulses delivered to Drosophila larvae.

Phases of circadian locomotor activity rhythms of adult Drosophila reared in constant darkness have been shown to be set by a light stimulus delivered as early as the first-instar larval stage. This implies that a circadian clock functions continuously throughout postembryonic development. The clock genes period (per) and timeless (tim) are expressed cyclically in the larval central nervous system of Drosophila, and daily oscillations of per expression persist throughout metamorphosis in a group of cells, which gives rise to the pacemaker cells underlying locomotor activity rhythms of adults. Therefore, PER and TIM cyclings in these neurons may be responsible for the phenomenon of "larval time-memory." In the absence of any evidence for the involvement of these genes in such a developmental clock, and because circadian-pacemaker functions are underanalyzed in terms of the functions during development, the authors tested the time-memory of a fast-clock period mutant. They show that dark-reared perS mutant individuals as well as wild-type flies can be entrained as larvae and that a brief light pulse given to such entrained larvae can induce phase shifts in animals of either genotype. However, the direction and magnitude of phase shifts were different between wild type and perS, suggesting that a clock under the control of period gene participates in the regulation of developmental time-memory. The authors show that the relevant clock can be entrained by two light input pathways, one involving the phospholipase C encoded by the norpA gene, the other mediated by the blue-light receptor cryptochrome. Phase shifts of molecular oscillations during the larval stage were smaller than those measured by adult behavior, suggesting molecularly transient responses during development.

Animals↗
PubMed2007

Drosophila melanogaster p24 genes have developmental, tissue-specific, and sex-specific expression patterns and functions.

Genes encoding members of the p24 family of intracellular trafficking proteins are present throughout animal and plant lineages. However, very little is known about p24 developmental, spatial, or sex-specific expression patterns or how localized expression affects function. We investigated these problems in Drosophila melanogaster, which contains nine genes encoding p24 proteins. One of these genes, logjam (loj), is expressed in the adult female nervous system and ovaries and is essential for oviposition. Nervous system-specific expression of loj, but not ovary-specific expression, rescues the behavioral defect of mutants. The Loj protein localizes to punctate structures in the cellular cytoplasm. These structures colocalize with a marker specific to the intermediate compartment and cis-Golgi, consistent with experimental evidence from other systems suggesting that p24 proteins function in intracellular transport between the endoplasmic reticulum and Golgi. Our findings reveal that Drosophila p24 transcripts are developmentally and tissue-specifically expressed. CG31787 is male-specifically expressed gene that is present during the larval, pupal, and adult stages. Female CG9053 mRNA is limited to the head, whereas males express this gene widely. Together, our studies provide experimental evidence indicating that some p24 genes have sex-specific expression patterns and tissue- and sex-limited functions.

Animals↗