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PubMed2004

Developmental stage differences in chromatin subdomains of the beta-globin locus.

The mammalian beta-globin loci each contain a family of developmentally expressed genes, and a far upstream regulatory element, the locus control region (LCR). In adult murine erythroid cells, the LCR and the transcribed beta-globin genes exist within domains of histone acetylation and RNA polymerase II (pol II) is associated with them. In contrast, the silent embryonic genes lie between these domains within hypoacetylated chromatin, and pol II is not found there. We used chromatin immunoprecipitation and real-time PCR to analyze histone modification and pol II recruitment to the globin locus in human erythroid K562 cells that express the embryonic epsilon-globin gene but not the adult beta-globin gene. H3 and H4 acetylation and H3 K4 methylation were continuous over a 17-kb region including the LCR and the active epsilon-globin gene. The level of modification varied directly with the transcription of the epsilon-globin gene. In contrast, this region in nonerythroid HeLa cells lacked these modifications and displayed instead widespread H3 K9 methylation. pol II was also detected continuously from the LCR to the epsilon-globin gene. These studies reveal several aspects of chromatin structure and pol II distribution that distinguish the globin locus at embryonic and adult stages and suggest that both enhancer looping and tracking mechanisms may contribute to LCR-promoter communication at different developmental stages.

Chromatin↗
PubMed1998

Response of preimplantation murine embryos to heat shock as modified by developmental stage and glutathione status.

Objectives were to characterize developmental changes in response to heat shock in the preimplantation mouse embryo and to evaluate whether ability to synthesize glutathione is important for thermal resistance in mouse embryos. Heat shock (41 degrees C for 1 or 2 h) was most effective at disrupting development to the blastocyst stage when applied to embryos at the 2-cell stage that were delayed in development. Effects of heat shock on ability of embryos to undergo hatching were similar for 2-cell, 4-cell, and morula stage embryos. The phenomenon of induced thermotolerance, for which exposure to a mild heat shock increases resistance to a more severe heat shock, depended upon stage of development and whether embryos developed in vitro or in vivo. In particular, induced thermotolerance was observed for morulae derived from development in vivo but not for 2-cell embryos or morulae that developed in culture. Administration of buthionine sulfoximine to inhibit glutathione synthesis did not increase thermal sensitivity of 2-cell embryos or morulae but did reduce subsequent development of 2-cell embryos at both 37 degrees and 41 degrees C. In summary, changes in the ability of 2-cell through morula stages to continue to develop following a single heat shock were generally minimal. However, 2-cell embryos delayed in development had reduced thermal resistance, and therefore, maternal heat stress may be more likely to cause mortality of embryos that are already compromised in development. There were also developmental changes in the capacity of embryos to undergo induced thermotolerance. Glutathione synthesis was important for development of embryos but inhibition of glutathione synthesis did not make embryos more susceptible to heat shock.

Adaptation, Physiological↗
PubMed2005

Developmental stage determines the effects of MYC in the mammary epithelium.

Epidemiological findings suggest that the consequences of a given oncogenic stimulus vary depending upon the developmental state of the target tissue at the time of exposure. This is particularly evident in the mammary gland, where both age at exposure to a carcinogenic stimulus and the timing of a first full-term pregnancy can markedly alter the risk of developing breast cancer. Analogous to this, the biological consequences of activating oncogenes, such as MYC, can be influenced by cellular context both in terms of cell lineage and cellular environment. In light of this, we hypothesized that the consequences of aberrant MYC activation in the mammary gland might be determined by the developmental state of the gland at the time of MYC exposure. To test this hypothesis directly, we have used a doxycycline-inducible transgenic mouse model to overexpress MYC during different stages of mammary gland development. Using this model, we find that the ability of MYC to inhibit postpartum lactation is due entirely to its activation within a specific 72-hour window during mid-pregnancy; by contrast, MYC activation either prior to or following this 72-hour window has little or no effect on postpartum lactation. Surprisingly, we find that MYC does not block postpartum lactation by inhibiting mammary epithelial differentiation, but rather by promoting differentiation and precocious lactation during pregnancy, which in turn leads to premature involution of the gland. We further show that this developmental stage-specific ability of MYC to promote mammary epithelial differentiation is tightly linked to its ability to downregulate caveolin 1 and activate Stat5 in a developmental stage-specific manner. Our findings provide unique in vivo molecular evidence for developmental stage-specific effects of oncogene activation, as well as the first evidence linking MYC with activation of the Jak2-Stat5 signaling pathway.

Animals↗
PubMed2000

Modification of murine adult haemopoiesis and response to methyl nitrosourea following exposure to radiation at different developmental stages.

PURPOSE: To investigate the hypothesis that the developmental phase at which an individual encounters radiation damage affects its long-term sensitivity to a subsequent tumourigenic insult. MATERIALS AND METHODS: Either the pregnant C57B16 mouse was exposed to 137Cs gamma-rays at 4 or 15 days post-conception (embryonic and foetal stages respectively) or BDF1 offspring were irradiated at 4 or 21 days of age (neonatal and juvenile stages). Offspring were either assayed for changes in bone marrow stem cells and committed progenitors at 6, 12 and 18 weeks of age, or injected with the chemical carcinogen methyl nitrosourea (MNU) at 10 weeks of age and monitored for onset of neoplasia. RESULTS: Gamma-irradiation induced a persistent long-term deficit in stem cells in all irradiated animals, with the foetal stage appearing most radiosensitive. However, femoral cellularity, committed progenitor cell numbers and peripheral blood counts were unaffected. When offspring were exposed to MNU, the incidence of malignancy was significantly enhanced in animals irradiated at the foetal, neonatal and juvenile stages. CONCLUSIONS: This study has shown that exposure to ionizing radiation at the foetal, neonate or juvenile stages of development induces residual haemopoietic damage and increases oncogenic susceptibility to a subsequent exposure to MNU.

Age Factors↗
PubMed2006

Developmental stage- and DNA damage-specific functions of C. elegans FANCD2.

In this study, we set out to investigate the role of Fanconi anemia complementation group D2 protein (FANCD2) in developmental stage-specific DNA damage responses in Caenorhabditis elegans. A mutant C. elegans strain containing a deletion in the gene encoding the FANCD2 homolog, FCD-2, exhibited egg-laying defects, precocious oogenesis, and partial defects in fertilization. The mutant strain also had a lower hatching rate than the wild-type after gamma-irradiation of embryos, but not after the irradiation of pachytene stage germ cells. This mutation sensitized pachytene stage germ cells to the genotoxic effects of photoactivated psoralen, as seen by a greatly reduced hatching rate and increased chromosomal aberrations. This mutation also enhanced physiological M-phase arrest and apoptosis. Taken together, our data reveal that the C. elegans FANCD2 homolog participates in the repair of spontaneous DNA damage and DNA crosslinks, not only in proliferating cells but also in pachytene stage cells, and it may have an additional role in double-stranded DNA break repair during embryogenesis.

Animals↗
PubMed1994

Plasmodium gallinaceum: differential lysis of two developmental stages of malaria sporozoites by the alternative pathway of complement.

During sporogonic development of Plasmodium gallinaceum in the mosquito vector, two developmentally distinct sporozoite stages can be isolated. Sporozoites obtained from oocysts in abdomens of mosquitoes 10 days after an infective blood meal are poorly infectious to the vertebrate host (chicken); days later, sporozoites isolated from mosquito salivary glands are highly infectious. In a first step toward understanding the physiologic basis of this developmentally regulated infectivity to the vertebrate host, we determined the relative resistance of the two sporozoite stages to lysis by the complement system of the vertebrate host. Whereas 86% of oocyst sporozoites were lysed when incubated in fresh chicken serum in vitro, only 24% of salivary gland sporozoites were lysed under identical incubation conditions. Preincubation of oocyst sporozoites in a homogenate of female Aedes aegypti salivary glands did not diminish their susceptibility to lysis by serum, indicating that lysis was mediated by the interaction of serum factors with parasite-specific molecules. The lytic activity of fresh chicken serum was abrogated by incubating for 45 min at 56 degrees C or chelating with EDTA. Fresh chicken serum specifically depleted of Ca2+, by chelating with EGTA in the presence of Mg2+, retained its ability to lyse oocyst sporozoites. The lysis of salivary gland sporozoites mediated by chicken antisporozoite serum is abrogated by EGTA, indicating that the antibody-dependent complement pathway in chicken serum is blocked by EGTA. Because oocyst sporozoite lysis by serum was heat sensitive and Mg2+ dependent, but Ca2+ independent, we conclude that lysis was mediated by the alternative pathway of complement.(ABSTRACT TRUNCATED AT 250 WORDS)

Aedes↗
PubMed1978

[Cytochemical study of various stages of life cycle of Toxoplasma gondii. 11. oxidation-reduction enzymes in the parasites during developmental stages in cat's intestines].

Dehydrogenases of glycolysis, Krebs' cycle and pentose phosphate shunt were investigated in the intestinal stages of T. gondii. The "oval stages" appeared to display the activity of all the enzymes studied differing in this from merozoites and macrogametocytes. The macrogametocytes displayed very low, if any, activity of the enzymes studied, even the mature parasites. Immediately after fertilization, sharp shifts were observed in the oxidative metabolism of the zygote: from very low or negative it became moderate to strong. This may be suggestive of the changes in metabolic requirements of the zygote which is no longer an intracellular parasite. In this respect macrogametocytes and zygotes of Toxoplasma resemble the corresponding stages of chicken and rabbit intestinal coccidia of the genus Eimeria.

Animals↗
PubMed1977

[Cytochemical study of the different stages in the life cycle of Toxoplasma gondii. IX. The polysaccharides and lipids in the parasites at developmental stages from the cat intestine].

Amylopectin was detected in all the stages examined. In the oval stages the minute granules of PAS-positive material were seen in the cytoplasm when examined on fresh-frozen sections. In merozoites, amylopectin was more conspicuous with maturation. The residual body of microgametocytes contain large amounts of amylopectin; no polysaccharide was visualized in microgamete bodies. Amylopectin was most abundant in macrogametocytes and zygotes. However, no peripheral position of PAS-positive "plastic granules" (wall-forming bodies), so characteristic of other coccidia and revealed by the electron microscopy for T. gondii macrogametocytes, was seen. Acid mucopolysaccharides in the macrogametocyte were detected in the central zone, leaving the periphery of the cell unstained. Very small, if any, amounts of lipids were detected in asexual stages of T. gondii. Unlike, large accumulation of lipid droplets were seen in growing macrogametocytes suggesting the involvement of lipids along with amylopectin in the metabolism of oocysts later discharged from the host body.

Amylopectin↗
PubMed2003

Molecular cloning and tissue-specific, developmental-stage-specific, and hormonal regulation of IGFBP3 gene in zebrafish.

The biological functions of insulin-like growth factor (IGF) I and II are modulated by a family of IGF-binding proteins (IGFBPs) in complex IGF-dependent and IGF-independent pathways. For further understanding of the actions of IGFs, some of these binding proteins have been cloned and characterized. We report the molecular cloning of IGFBP-3 cDNA for zebrafish. The tissue-specific and developmental stage-specific expression of IGFBP-3 and the hormonal regulation of its expression have also been determined by comparative reverse transcription polymerase chain reaction. Zebrafish IGFBP-3 cDNA contains an open reading frame of 879 bp, encoding a polypeptide of 293 amino acid residues. Results of this analysis revealed high levels of IGFBP-3 messenger RNA in ovary and fin tissue. Expression of IGFBP-3 mRNA was throughout the entire embryonic development, with the highest level of expression observed at 36 hours after the onset of development. Elevated levels of expression of IGFBP-3 were observed 24 hours after injection with IGF-I and 48 hours with IGF-II or insulin. These results suggest that the expression of IGFBP3 gene might be modulated by IGF-I, IGF-II, and insulin.

Amino Acid Sequence↗
PubMed1993

P-glycoprotein regulates chemosensitivity in early developmental stages of the mouse.

The multidrug resistance (MDR) P-glycoprotein (P-gp) is an active transporter associated with chemoresistance of tumor cells. A fundamental aspect not yet entirely clarified is the physiological role of MDR-P-gp in normal mammalian tissues. In this paper we report that multidrug (chemo)resistance is already present in mouse oocytes and early cleavage embryos. Expression of MDR-specific P-gp is detectable by antibody (C219) staining from the primary oocyte onward to the eight-cell embryo. MDR-mRNA is demonstrated in mature oocytes using an Mdr1-specific cDNA probe. Functional activity of P-gp is shown by the efficacy of MDR reversers (verapamil or quinidine) in enhancement of: 1) drug accumulation (daunomycin) in all stages investigated, 2) drug cytotoxicity (daunomycin or mitomycin c-induced developmental impairment) in two-cell embryos cultured for 24 h, and 3) drug cytokinesis-blocking activity (cytochalasin D; our recent findings demonstrate cytochalasins to be substrates for P-gp and to indicate the presence of MDR by their microfilament-disrupting action on cycling cells) in four- and eight-cell embryos cultured for 24 h. Furthermore, functional involvement of P-gp in vivo is demonstrated. Concurrent administration of verapamil increases doxorubicin-induced developmental impairment in the zygote stage during the first cleavage cycle in pregnant females. Results provide evidence that MDR-P-gp has an efficient protective function in early reproduction.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Expression and function of cell adhesion molecules on fetal liver, cord blood and bone marrow hematopoietic progenitors: implications for anatomical localization and developmental stage specific regulation of hematopoiesis.

The mechanism of localization, migration, and regulation of hematopoiesis at different stages of ontogeny is not well understood, but may relate to the specific adhesive interactions between hematopoietic stem cells and their microenvironment at different ontogenic stages. We studied the expression of cell adhesion molecules (CAM) on fetal liver (FL), umbilical cord blood (UCB) and adult bone marrow (ABM) CD34+ cells, and the adhesion of committed progenitors (CFC) from all three sources to ABM stromal layers and purified extracellular matrix proteins. Compared to ABM CFC, significantly more UCB CFC and fewer FL CFC adhered to ABM stroma. Adhesion of FL CFC to fibronectin (FN), the 75 kD RGD containing FN fragment and the 33-66 kD COOH-terminal heparin binding FN fragment was also significantly less than that of ABM CFC. Like ABM CFC, the adhesion of FL CFC was mediated through alpha4beta1 and alpha5beta1 integrins. Of note, more FL CD34+ cells expressed alpha5 integrins and the number of alpha4, alpha5 and beta1 integins per cell (mean channel frequency) was similar or higher for FL CD34+ cells than ABM CD34+ cells. Further, treatment of FL CFC with a beta1 integrin activating antibody (8A2), increased adhesion of FL CFC to FN to the same level as that of 8A2 treated ABM CFC. This suggests that the alpha4beta1 and alpha5beta1 integrins on FL CD34+ cells may be present in a low avidity/affinity state. We also show that unlike ABM, FL CD34+ cells expressed alpha2 and that approximately 20% FL CFC adhered to collagen IV. Further, alpha2beta1 integrin on FL CFC was functional since their engagement, either by adhesion to collagen IV or through blocking alpha2 antibodies, transmitted proliferation inhibitory signals. In contrast to alpha4b and alpha5beta1 integrin dependent adhesion, alpha2beta1 dependent adhesion of FL CFC to collagen IV was not enhanced after treatment with 8A2. The reason for this is not clear but suggests that alpha2 integrins on FL CFC are maximally activated. This novel adhesive interaction with collagen IV, reminiscent of that described for CML progenitors, may have a role in the extramedullary localization of FL hematopoiesis or its developmental stage-specific regulation by its microenvironment. Studies to evaluate these possibilities are underway.

Adult↗
PubMed1969

[Studies On Lactic Dehydrogenase Activities In Developmental Stages Of Fertilized Eggs Of Ascaris Lumbricoides]

The lactic dehydrogenase activities of Ascaris lumbricoides have been assayed according to the developmental course of the fertilized eggs compared with the unfertilized eggs. Experimental procedures were modified that of Wroblewski and La Due's method with use of diphosphopyridine nucleotide reduced form(DPNH). Sodium pyruvate and lactic dehydrogenase, the specific activities were expressed as DPNH unit per mg protein by method of Kornberg's. The experimental results are as follaws: 1. Lactic dehydrogenase activity in fertilized eggs of Ascaris are significantly increased from morula stage and its optimal pH is in 3.4 degrees. While any activities were not observed in unicell stage of fertilized eggs and unfertilized eggs. 2. Water soluble protein of fertilized eggs of Ascaris were varied in their amount during their developmental process. The amont of protein in tadpole stage eggs have increased to 1.3 times more than that of cleavage stage eggs. 3. However the amounts of water soluble protein in unfertilized eggs are revealed to one-third less than that of fertlized eggs. 4. The specific activity of lactic dehydrogenase in tadpole stage eggs are decreased to one third less than those of morula stage eggs during development, the stage is considered to be as a growth criteria in developmental process, as on this point the activity of aerobic cytochrome coxidase and cyclophorase begin to increase respectively.

Journal Article↗
PubMedDate not supplied

Central hemodynamics in the developmental stage of spontaneous hypertension in the unanesthetized rat.

The hemodynamic alterations associated with the developmental phase of high blood pressure were investigated in the spontaneously hypertensive rat (SHR). All hemodynamic measurements were made in unanesthetized, unrestrained SHR and Wistar-Kyoto (WKY) rats instrumented with chronic electromagnetic flow probes on the ascending aorta and arterial pressure catheters. Rats were studied at 30-41 days, 80 days, and 120 days of age. Hemodynamics of SHRs and WKYs in the 30-41 day group were monitored daily. Spontaneously hypertensive rats demonstrated a higher cardiac index than WKYs (p less than 0.05) from 32 through 41 days of age. Total peripheral resistance (TPR) was not elevated in SHRs at this time. Heart rate and stroke index were elevated in SHRs (p less than 0.05) from 34 through 41 days, however, stroke volume was not. At 80 and 120 days SHRs had higher mean arterial pressure (MAP) and TPR than WKYs (p less than 0.05), although cardiac index was not significantly different. This hemodynamic pattern of a hyperkinetic circulation prior to the development of hypertension supports the theory of total body autoregulation. A transient increase in cardiac index precedes an increase in TPR, which then normalizes cardiac index while elevating MAP.

Aging↗
PubMed1993

Effects of developmental stage and tissue type on embryo/fetal DNA distributions and 5-fluorouracil-induced cell-cycle perturbations.

Cell-cycle analysis of nuclei obtained from the circulating erythroblasts (gestational day [GD] 11-16), livers (GD 14-19), and whole embryos (GD 10-13) or remaining (extrahepatic) tissues (GD 14-16) of rat embryos/fetuses revealed age- and tissue-dependent variations in the relative percentages of cells in the G0/G1, S, and G2/M phases of the cell cycle. With development, the rate of cell proliferation declined resulting in decreases in the relative percentage of S-phase cells and increases in the G0/G1 percentage, while the percentage of G2/M-phase cells remained relatively constant. Comparing tissue cell-cycle profiles during development, erythroblasts exhibited the most rapid age-dependent decline in S-phase percentage (from 75% at GD 11 to 8% by GD 14), embryos/extrahepatic tissues exhibited a more gradual reduction (from 55% at GD 10 to 14% by GD 15), while the hepatic isolates exhibited a relatively constant S-phase percentage of approximately 40% from GD 14 to GD 18 before decreasing to 23% at GD 19. These age-dependent variations suggest that cell-cycle distribution may be useful in staging embryogenesis and in detecting abnormal development. To determine how these developmental and organ-specific cell-cycle variations affect toxic response, we sampled GD 11-13 embryos 6 hr after maternal administration of a teratogenic dose of 5-fluorouracil (5-FU), a thymidylate synthetase inhibitor that induces S-phase accumulation. The results indicate that, on a relative basis, the amount of induced S-phase accumulation in erythroblasts and whole embryos 6 hr postdosing increased with development.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Expression profiling using random genomic DNA microarrays identifies differentially expressed genes associated with three major developmental stages of the protozoan parasite Leishmania major.

To complete its life cycle, protozoan parasites of the genus Leishmania undergo at least three major developmental transitions. However, previous efforts to identify genes showing stage regulated changes in transcript abundance have yielded relatively few. Here we used expression profiling to assess changes in transcript abundance in three stages: replicating promastigotes and infective non-replicating metacyclics, which occur in the sand fly vector, and in the amastigote stage residing with macrophage phagolysosomes in mammals. Microarrays were developed containing 11,484 PCR products that included a number of known genes and 10,464 random 1 kb genomic DNA fragments. Arrays were hybridized in triplicate and genes showing two-fold or greater changes in 2/3 experiments were scored as differentially expressed. Remarkably, only about one percent of the DNAs expression varied by this criteria, in either stage comparison. Northern blot analysis confirmed the predicted change in mRNA abundance for most of these (68%). This set of genes included most of those previously identified in the literature as differentially regulated as well as a number of novel genes. Notably, Leishmania maxicircle transcripts showed strong up-regulation in metacyclic and amastigote parasites, probably associated with changes in parasite energy metabolism. However, current data suggest that expression profiling using shotgun DNA libraries significantly underestimates the extent of regulated transcripts.

Animals↗
PubMed1999

Identification of regulatory regions driving the expression of the Drosophila spalt complex at different developmental stages.

The zinc finger transcription factors Spalt and Spalt-related have been implicated in multiple developmental processes. In the wing they are regulated by the secreted protein Decapentaplegic and participate in the positioning of the wing veins. The function of Spalt has been also analyzed during tracheal development and embryonic segmentation. Here, we present the isolation and characterization of novel spalt/spalt-related alleles, which analysis indicates that these genes cannot substitute for each other in the developmental processes studied. The mutants present embryonic or pupal lethality, with phenotypes consistent with the loss of spalt function. We also present a detailed functional analysis of the DNA regions implicated in the regulation of these genes. This regulation is complex, integrating the information from both negative and positive regulators, and it is modular, with discrete fragments of DNA directing expression to discrete regions in embryonic and larval tissues.

Alleles↗
PubMed2005

Gene expression in bovine embryos derived from oocytes with different developmental competence collected at the defined follicular developmental stage.

The aim of this study was to compare the expression of selected genes in bovine embryos developed from oocytes with different developmental competence. Four oocyte populations were collected, separately either from small (2-5 mm) or medium (6-10 mm) follicles, in the growth/stagnation (G/S) or dominance/regression (D/R) stage of the first follicular wave. They were matured, fertilized and cultured to D7 or D8 blastocysts by a standard protocol. Poly (A)+ mRNA was extracted from pooled blastocysts and the expression of bax-alpha (Bax), connexin 43 (Cx 43) and connexin 31 (Cx 31) was estimated using real-time RT-PCR. The cleavage rates were significantly higher in oocytes collected from both medium and small follicles, (p < or = 0.05 and p < or = 0.01, respectively) in the G/S than in the D/R stage. There were no significant differences in the D7 blastocyst rates between oocytes from both medium and small follicles in the G/S or D/R stage. But the D8 blastocyst rate was significantly higher in oocytes from small follicles in the G/S stage compared with those in the D/R stage. The relative abundance of Bax and Cx 31 made no significant difference in both D7 and D8 blastocysts developed from oocytes collected from medium or small follicles in the G/S or D/R stages. But the relative abundance of the Cx 43 transcript was significantly higher in D8 blastocysts developed from oocytes collected from both medium and small follicles in the G/S stage compared with those in the D/R stage. We conclude that the relative abundance of Cx 43 can be used as a marker of developmental potential for embryos derived from oocytes with different developmental competence because the level of Cx 43 transcript was greater in embryos derived from oocytes with greater developmental competence compared with those derived from oocytes with lesser developmental competence.

Animals↗