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PubMed2003

Temporally dynamic response to Wingless directs the sequential elaboration of the proximodistal axis of the Drosophila wing.

The Drosophila wing imaginal disc gives rise to three main regions along the proximodistal axis of the dorsal mesothoracic segment: the notum, proximal wing, and wing blade. Development of the wing blade requires the Notch and wingless signalling pathways to activate vestigial at the dorsoventral boundary. However, in the proximal wing, Wingless activates a different subset of genes, e.g., homothorax. This raises the question of how the downstream response to Wingless signalling differentiates between proximal and distal fate specification. Here, we show that a temporally dynamic response to Wingless signalling sequentially elaborates the proximodistal axis. In the second instar, Wingless activates genes involved in proximal wing development; later in the third instar, Wingless acts to direct the differentiation of the distal wing blade. The expression of a novel marker for proximal wing fate, zfh-2, is initially activated by Wingless throughout the "wing primordium," but later is repressed by the activity of Vestigial and Nubbin, which together define a more distal domain. Thus, activation of a distal developmental program is antagonistic to previously established proximal fate. In addition, Wingless is required early to establish proximal fate, but later when Wingless activates distal differentiation, development of proximal fate becomes independent of Wingless signalling. Since P-element insertions in the zfh-2 gene result in a revertable proximal wing deletion phenotype, it appears that zfh-2 activity is required for correct proximal wing development. Our data are consistent with a model in which Wingless first establishes a proximal appendage fate over notum, then the downstream response changes to direct the differentiation of a more distal fate over proximal. Thus, the proximodistal domains are patterned in sequence and show a distal dominance.

Animals↗

PubMed1989

Molecular analysis of a developmentally regulated gene required for Dictyostelium aggregation.

We have previously shown that the developmentally regulated gene D2 is induced during aggregation by pulses of cAMP, which act via the cell surface receptor and consequent signal transduction pathways (W. Rowekamp and R.A. Firtel, 1980, Dev. Biol. 79, 409-418; S.K.O. Mann and R.A. Firtel, 1987, Mol. Cell. Biol. 7, 458-469; S.K.O. Mann, C. Pinko, and R.A. Firtel, 1988, Dev. Biol., in press). In this manuscript, we compare the complete derived amino acid sequence for D2 to two cloned and sequenced eukaryotic esterases and examine the requirement of the D2 gene product for development. Amino acid sequence data comparisons suggest that D2 encodes a serine esterase with strong sequence identity to Torpedo acetylcholine esterase and a Drosophila esterase. The protein has a putative leader sequence, suggesting that it is shunted into vesicles. Using an antisense gene construct driven by a Discoidin I promoter, whose transcriptional activity depends on the growth conditions of the cells, we show that inhibition of D2 mRNA accumulation results in an abnormal developmental program that includes the absence of normal streaming and incomplete aggregate formation and subsequent development. We suggest that D2 encodes an esterase function required for proper aggregation and subsequent development.

Acetylcholinesterase↗

PubMed1995

alpha-Crystallin polypeptides in developing chicken lens cells.

We provide evidence that the different cells that form the chicken lens have isoelectric variants of alpha-crystallins at early and late developmental stages. We separated the alpha A and alpha B-crystallin subclasses by sodium dodecylsulphate polyacrylamide gel electrophoresis and then further resolved each by isoelectric focusing and assays with specific anti alpha-crystallin antibodies. We found that the annular pad, cortical and nuclear fibers, as well as the epithelial cells, contain alpha A and alpha B native chains and their respective isoelectric variants. These results on adult and embryonic lenses obtained a short time after the onset of alpha-crystallin expression suggest that lens cells, having different phenotypes, are able to produce post-translational modifications of the alpha A and alpha B chains as a part of their developmental program.

Animals↗

PubMed1997

Construction and characterization of the soybean leaf metalloproteinase cDNA.

The cloning and analysis of a cDNA clone encoding the soybean metalloproteinase obtained by polymerase chain reaction (PCR) and the rapid amplification of cDNA ends (RACE) reaction are described. The cDNA was constructed from poly(A)+ RNA isolated from 15-17 day old leaves. The deduced amino acid sequence of the cDNA reveals that the plant metalloproteinase is synthesized as a preproenzyme and the proenzyme form shares a structural motif, responsible for maintenance of inactive zymogen, with the matrix metalloproteinase (e.g. collagenase) family of enzymes from vertebrate origin. Northern and Western blot analysis demonstrated that the metalloproteinase transcript and protein are under a strict developmental program in that both are expressed only in leaf tissue and in a temporal fashion. The physiological function of the metalloproteinase still remains unclear although the data suggest that the enzyme is extracellular and a portion of the mature form of the enzyme is tightly bound to the cell wall.

Amino Acid Sequence↗

PubMed2003

Transgenic overexpression of the oncofetal RNA binding protein KOC leads to remodeling of the exocrine pancreas.

BACKGROUND & AIMS: To elucidate the function of the oncofetal RNA-binding protein, K-homologous (KH) domain containing protein overexpressed in cancer (KOC), we studied the effect of a constitutive reexpression of KOC in transgenic mice. METHODS: Transgenic mouse lines expressing KOC under the control of the mouse metallothionein promoter were generated and were shown to express the 69-kilodalton protein. Two mouse lines with moderate to strong gene expression of the transgene were further analyzed. RESULTS: The pancreas of KOC-transgenic mice showed progressive morphologic alterations, including an increased proliferation of acinar cells, acinar-ductal metaplasia, net loss of acinar tissue, and the appearance of numerous interstitial cells. Acinar-ductal metaplasia led to the development of duct-like structures exhibiting the characteristics of normal intralobular ducts. Interstitial cells expressed markers of endocrine or ductal differentiation. Nerve growth factor alpha (NGF-alpha) and the GTPase kir/Gem were identified as potential targets of KOC by expression profiling analyses. CONCLUSIONS: Reexpression of KOC in the transgenic model is apparently incompatible with the maintenance of a fully differentiated, adult acinar phenotype and may lead to a more fetal ductal phenotype via acinar-ductal metaplasia. This and the appearance of interstitial cells with a ductal and endocrine differentiation capacity suggest that transgenic reexpression of the oncofetal gene KOC may recapitulate a developmental program active during embryogenesis.

Animals↗

PubMed1999

Expansion of Pdx1-expressing pancreatic epithelium and islet neogenesis in transgenic mice overexpressing transforming growth factor alpha.

BACKGROUND & AIMS: The progenitor cells responsible for transforming growth factor (TGF)-alpha-induced pancreatic ductal metaplasia and neoplasia remain uncharacterized. During pancreatic development, differentiated cell types arise from ductal progenitor cells expressing the Pdx1 homeodomain transcription factor. The aims of this study were, first, to evaluate the role of Pdx1-expressing stem cells in MT-TGFalpha transgenic mice, and second, to further characterize cell proliferation and differentiation in this model. METHODS: To assess Pdx1 gene expression in normal and metaplastic epithelium, we performed in vivo reporter gene analysis using heterozygous Pdx1(lacZ/+) and bigenic Pdx1(lacZ/+)/MT-TGFalpha mice. RESULTS: Pdx1(lacZ/+)/MT-TGFalpha bigenics showed up-regulated Pdx1 expression in premalignant metaplastic ductal epithelium. In addition to Pdx1 gene activation, TGF-alpha-induced metaplastic epithelium demonstrated a pluripotent differentiation capacity, as evidenced by focal expression of Pax6 and initiation of islet cell neogenesis. The majority of Pdx1-positive epithelial cells showed no expression of insulin, similar to the pattern observed during embryonic development. CONCLUSIONS: Overexpression of TGF-alpha induces expansion of a Pdx1-expressing epithelium characterized by focal expression of Pax6 and initiation of islet neogenesis. These findings suggest that premalignant events induced by TGF-alpha in mouse pancreas may recapitulate a developmental program active during embryogenesis.

Animals↗

PubMed2000

Induction and development of winter larval diapause in a drosophilid fly, Chymomyza costata.

Photoperiodic response during induction of larval hibernal diapause of Chymomyza costata was characterized and the course of diapause development was analyzed in the laboratory. C. costata becomes sensitive to photoperiodic stimuli during an unspecified stage of its early development (embryo, 1st larval instar); the sensitivity gradually increases during the 2nd and early 3rd larval instars and reaches its maximum just before the moment when it abruptly ceases at the age of 15-19 days after oviposition. Diapause intensifies during a period of 2-3 weeks after induction and, later, is maintained without apparent development until death (between 150 and 250 days) under 18 degrees C and a short-day photoperiod (L10:D14, SD). Diapause may be terminated in a horotelic process by exposure to a low temperature (2 degrees C) during which larvae subsequently (1) synchronize their post-diapause development (requires up to 14 days of chilling), (2) lose photoperiodic sensitivity (2 months), and finally (3) terminate diapause (5 months). Alternatively, diapause may be terminated in a tachytelic process by exposure to a high temperature (18 degrees C) and long-day photoperiod (L16:D8, LD) during which no synchronization occurs and pupariation takes place after a mean of 25.2 days (with a broad range from 8 to more than 50 days). Larvae that are transferred from LD to SD during their sensitive period switch their developmental programming from pupariation to diapause. Proliferation of adult primordial structures (imaginal discs, neuroblasts) slows down within 1 day after transfer. In contrast, whole body growth continues for at least 3 days before its rate slows down and matches the rate characteristic for SD conditions.

Journal Article↗

PubMed2000

Circadian component influences the photoperiodic induction of diapause in a drosophilid fly, Chymomyza costata.

The last-instar larvae of a drosophilid fly, Chymomyza costata enter diapause in response to the dark-phases longer than 9 h (Yoshida, T., Kimura, M.T., 1995. The photoperiodic clock in Chymomyza costata. Journal of Insect Physiology 41, 217-222). In order to switch the developmental programming of the sensitive larvae from continuous development to diapause, after they were transferred from the short (8 h) to the long (14 h) dark-phase, significantly less time (1-2 days) was required when the dark-phase was abruptly and asymmetrically extended into the evening, than when it was extended symmetrically into both morning and evening (2-3 days), or asymmetrically into the morning hours (4-6 days). Diapause was also induced in 40-70% of sensitive larvae that were reared under the gradually shortening light-phase (from 16 h to 2 h, by 1 h in each cycle), despite that the dark-phase remained constant and short (8 h). Larvae developed continuously, however, when reared under the gradually extending light-phase (from 16 h to 24 h) and a constantly short dark-phase. We interpret such results, with the help of the two-oscillator model of circadian rhythmicity (Pittendrigh, C.S., Daan, S., 1976. A functional analysis of circadian pacemakers in nocturnal rodents. V. Pacemaker structure: A clock for all seasons. Journal of Comparative Physiology A 106, 333-355), as indicating that two mutually coupled oscillators (evening and morning) differing in their entrainability may participate in measuring of the dark-phase duration. The levels of dopamine (DA) and serotonin (5-HT) in the larval CNS transiently increased (by up to 20%) after the dusk, while no apparent change was observed during the dawn. The dusk-related increase was observed also after the asymmetric extension of the dark-phase into evening, while the asymmetric extension into morning had no effect on the levels of the DA and 5-HT.

Journal Article↗

PubMed1995

Effect of recombinant human erythropoietin on the switchover from fetal to adult hemoglobin synthesis in preterm infants.

To determine whether recombinant erythropoietin (r-HuEpo) administered to very low birth weight infants could increase hemoglobin F synthesis, or delay its developmentally programmed decline, we determined serially the synthesis of hemoglobins A and F in 15 preterm infants receiving either a placebo or r-HuEpo. There was no difference between the two groups in the proportion of hemoglobin F being synthesized in relation to postconceptional age.

Analysis of Variance↗

PubMed2003

Somatic selection for and against cancer.

In multicellular organisms, cells cooperate within a well-defined developmental program. Cancer is a breakdown of such cooperation: cells mutate to phenotypes of uncoordinated proliferation. We study basic principles of the architecture of solid tissues that influence the rate of cancer initiation. In particular, we explore how somatic selection acts to prevent or to promote cancer. Cells with mutations in oncogenes or tumor suppressor genes often have increased proliferation rates. Somatic selection increases their abundance and thus enhances the risk of cancer. Many potentially harmful mutations, however, increase the probability of triggering apoptosis and, hence, initially lead to cells with reduced net proliferation rates. Such cells are eliminated by somatic selection, which therefore also works to reduce the risk of cancer. We show that a tissue organization into small compartments avoids the rapid spread of mutations in oncogenes and tumor suppressor genes, but promotes genetic instability. In small compartments, genetic instability, which confers a selective disadvantage for the cell, can spread by random drift. If both deleterious and advantageous mutations participate in tumor initiation, then we find an intermediate optimum for the compartment size.

Animals↗

PubMed1997

Molecular/cellular biology of the heat stress response and its role in agent-induced teratogenesis.

Available data indicate that heat shock proteins act as chaperones under non-stress conditions by assisting in: (1) the folding of newly synthesized proteins, (2) the intracellular translocation of proteins, and (3) the function of other proteins. As we gain additional information concerning cellular physiology, we may find that heat shock proteins play a key role in many additional cellular functions. When cells experience thermal or chemical stress, heat shock proteins take on a new role, conserved from bacteria to humans, of protecting cells from the detrimental effects of stress. This latter role takes on added significance for the embryo in which the developmental program must be read linearly, with little opportunity to cycle backward to complete a missed segment of the program. Although circumstantial evidence clearly implicates heat shock proteins in protecting embryos from thermal stress, definitive evidence is still lacking. The challenge for the future is to obtain such definitive data. Ideally, such information will lead to new therapeutic paradigms that will afford protection to the human embryo/fetus exposed to thermal/chemical stress.

Animals↗

PubMed1990

Effects of heat and chemical stress on development.

Similarities in the means by which developmental defects are induced in vertebrates and Drosophila suggest that some kinds of defects may be induced by similar mechanisms. The similarities include the fact that heat and a group of chemicals that induce synthesis of heat-shock proteins induce defects in mammals, chickens, and flies. Different kinds of defects are even produced in one type of animal, depending on the precise timing of the environmental insult. The effectiveness of the environmental treatment in inducing defects depends on the genetic background of the animal as well as on past exposure to chemicals and heat. Developmental defects induced by heat in mice, rats, and flies can all be prevented by thermotolerance-inducing treatments. The basis for these effects has been studied at the molecular level in Drosophila, and the evidence indicates that these teratogens and the thermotolerance-inducing treatments affect the level or timing of expression of specific genes during critical periods in the developmental program.

Abnormalities, Drug-Induced↗

PubMed2004

Structure and function of eukaryotic DNA methyltransferases.

DNA methylation is a common epigenetic modification found in eukaryotic organisms ranging from fungi to mammals. Over the past 15 years, a number of eukaryotic DNA methyltransferases have been identified from various model organisms. These enzymes exhibit distinct biochemical properties and biological functions, partly due to their structural differences. The highly variable N-terminal extensions of these enzymes harbor various evolutionarily conserved domains and motifs, some of which have been shown to be involved in functional specializations. DNA methylation has divergent functions in different organisms, consistent with the notion that it is a dynamically evolving mechanism that can be adapted to fulfill various functions. Genetic studies using model organisms have provided evidence suggesting the progressive integration of DNA methylation into eukaryotic developmental programs during evolution.

Animals↗

PubMed1998

Regulation and execution of meiosis in Drosophila males.

In this chapter we review the regulation and execution of the meiotic cell divisions in the context of the developmental program that comprises Drosophila spermatogenesis. Male germ line cells undergoing meiosis are readily identifiable and are of a size and abundance that makes this system well suited for morphological characterizations of cell division. Furthermore, a wide range of molecular genetic techniques are available, facilitating mechanistic investigations. We present an overview of key stages in spermatogenesis and, in particular, meiosis. We consider the pathways controlling entry into the meiotic divisions in the context of established cell cycle regulators as well as newly identified loci required for meiotic entry. We then review the assembly and function of both the meiotic spindle and the contractile ring. We conclude with a consideration of questions and problems that await further investigation.

Animals↗

PubMed1984

Biochemical mechanism of glucocorticoid-and phenytoin-induced cleft palate.

The production of cleft palate by glucocorticoids and phenytoin is a complicated interference in a complex developmental program involving many genetic and biochemical processes. The H-2 histocompatibility region includes genes which affect (1) susceptibility to glucocorticoid- and phenytoin-induced cleft palate; (2) glucocorticoid receptor level in a variety of tissues including maternal and embryonic palates, adult thymuses, and lungs; and (3) the degree of inhibition of prostaglandin and thromboxane production by glucocorticoids and phenytoin in thymocytes. A gene linked to a minor histocompatibility locus (H-3) on the second chromosome also influences susceptibility to glucocorticoid- and phenytoin-induced cleft palate. Phenytoin is an alternate ligand for the glucocorticoid receptor affecting prostaglandin and/or thromboxane production. The capacity of glucocorticoids to induce cleft palate is correlated with their anti-inflammatory potency. At least some of the anti-inflammatory effects of glucocorticoids can be explained by the inhibition of prostaglandin and/or thromboxane release, which in turn could be caused by inhibition of arachidonic acid release from phospholipids. Similar mechanisms may be involved in cleft palate induction, as exogenous arachidonic acid injected into pregnant rats and mice at the same time as glucocorticoids reduces the teratogenic potency of the steroids, and indomethacin, an inhibitor of cyclooxygenase, blocks the corrective action of arachidonic acid. Glucocorticoids and phenytoin cause a delay in shelf elevation, and this delay is promoted by fetal membranes and the tongue. However, the cells of the medial edge epithelium are programmed to die whether contact is made with the apposing shelf or not. Glucocorticoids and phenytoin interfere with this programmed cell death, and this interference by both drugs seems to be glucocorticoid receptor mediated, to require protein synthesis, and to be related to arachidonic acid release.

Animals↗

PubMed2003

Genomic domains and regulatory elements operating at the domain level.

The sequencing of the complete genomes of several organisms, including humans, has so far not contributed much to our understanding of the mechanisms regulating gene expression in the course of realization of developmental programs. In this so-called "postgenomic" era, we still do not understand how (if at all) the long-range organization of the genome is related to its function. The domain hypothesis of the eukaryotic genome organization postulates that the genome is subdivided into a number of semiindependent functional units (domains) that may include one or several functionally related genes, with these domains having well-defined borders, and operate under the control of special (domain-level) regulatory systems. This hypothesis was extensively discussed in the literature over the past 15 years. Yet it is still unclear whether the hypothesis is valid or not. There is evidence both supporting and questioning this hypothesis. The most conclusive data supporting the domain hypothesis come from studies of avian and mammalian beta-globin domains. In this review we will critically discuss the present state of the studies on these and other genomic domains, paying special attention to the domain-level regulatory systems known as locus control regions (LCRs). Based on this discussion, we will try to reevaluate the domain hypothesis of the organization of the eukaryotic genome.

Animals↗

PubMed1999

Retinoids and mammalian development.

All vertebrate embryos require retinoic acid (RA) for fulfilment of the developmental program encoded in the genome. In mammals, maternal homeostatic mechanisms minimize variation of retinoid levels reaching the embryo. Retinol is transported as a complex with retinol-binding protein (RBP): transplacental transfer of retinol and its uptake by the embryonic tissues involves binding to an RBP receptor at the cell surface. Embryonic tissues in which this receptor is present also contain the retinol-binding protein CRBP I and the enzymes involved in RA synthesis; the same tissues are particularly vulnerable to vitamin A deficiency. In the nucleus, the RA signal is transduced by binding to a heterodimeric pair of retinoid receptors (RAR/RXR). In general, the receptors show functional plasticity, disruption of one RAR or RXR gene having minor or no effects on embryogenesis. However, genetic studies indicate that RXR alpha is essential for normal development of the heart and eye. Excess RA causes abnormalities of many systems; altered susceptibility to RA excess in mice lacking RAR gamma or RXR alpha suggests that the teratogenic signal is transduced through different receptors compared with physiological RA function in the same tissue.

Animals↗

PubMed2005

Large- and small-scale purification of mammalian 26S proteasomes.

The 26S proteasome is an ATP-dependent protease known to collaborate with ubiquitin, whose polymerization acts as a marker for regulated and enforced destruction of unnecessary proteins in eukaryotic cells. It is an unusually large multi-subunit protein complex, consisting of a central catalytic machine (called the 20S proteasome or CP/core particle) and two terminal regulatory subcomplexes, termed PA700 or RP/regulatory particle, that are attached to both ends of the central portion in opposite orientations to form an enzymatically active proteasome. To date, proteolysis driven by the ubiquitin-proteasome system has been shown to be involved in a diverse array of biologically important processes, such as the cell cycle, immune response, signaling cascades, and developmental programs; and the field continues to expand rapidly. Whereas the proteasome complex has been highly conserved during evolution because of its fundamental roles in cells, it has also acquired considerable diversity in multicellular organisms, particularly in mammals, such as immunoproteasomes, PA28, S5b, and various alternative splicing forms of S5a (Rpm 10). However, the details of the ultimate pathophysiological roles of mammalian proteasomes have remained elusive. This article focuses on methods for assay and purification of 26S proteasomes from mammalian cells and tissues.

Animals↗