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PubMed1997

Development of the kidney vasculature.

Renal vascularization and nephrogenesis occur simultaneously following a tightly regulated developmental program influenced by growth factors, extracellular matrix components and cell membrane receptors. Both processes of angiogenesis and vasculogenesis probably participate in the formation of renal vessels. The origin and fate of the various renal vascular cells and the molecular mechanisms that initiate and guide intrarenal vascularization are fundamental questions that remain to be answered.

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PubMed1999

Dictyostelium as model system for studies of the actin cytoskeleton by molecular genetics.

The actin cytoskeleton is an essential structure for most movements at the cellular and intracellular level. Whereas for contraction a muscle cell requires a rather static organisation of cytoskeletal proteins, cell motility of amoeboid cells relies on a tremendously dynamic turnover of filamentous networks in a matter of seconds and at distinct regions inside the cell. The best model system for studying cell motility is Dictyostelium discoideum. The cells live as single amoebae but can also start a developmental program that leads to multicellular stages and differentiation into simple types of tissues. Thus, cell motility can be studied on single cells and on cells in a tissue-like aggregate. The ability to combine protein purification and biochemistry with fairly easy molecular genetics is a unique feature for investigation of the cytoskeleton and cell motility. The actin cytoskeleton in Dictyostelium harbours essentially all classes of actin-binding proteins that have been found throughout eukaryotes. By conventional mutagenesis, gene disruption, antisense approaches, or gene replacements many genes that code for cytoskeletal proteins have been disrupted, and altered phenotypes in transformants that lacked one or more of those cytoskeletal proteins allowed solid conclusions about their in vivo function. In addition, tagging the proteins or selected domains with green fluorescent protein allows the monitoring of protein redistribution during cell movement. Gene tagging by restriction enzyme mediated integration of vectors and the ongoing international genome and cDNA sequencing projects offer the chance to understand the dynamics of the cytoskeleton by identification and functional characterisation of all proteins involved.

Actins↗

PubMed1999

Molecules on the sperm's route to fertilization.

In eutherian mammals billions of sperm are deposited at ejaculation in the female reproductive tract, but only a few thousand enter the oviduct. A few reach the ampulla at the time of fertilization and only one sperm fertilizes the egg. In most mammalian species the lower isthmus of the fallopian tubes has taken over the function of a reservoir in which sperm are stored under conditions that save sperm energy by suppressing motility and increase viability. Close to the time when the egg is ovulated into the ampulla, the sperm undergo a complex sequence of processes, named capacitation. Capacitation is a prerequisite for fertilization, enabling the sperm to recognize the egg and to respond to the egg signals in the appropriate manner. Sperm bind to the egg extracellular matrix, the zona pellucida, and upon binding undergo the acrosome reaction, followed by the passage of the zona pellucida and binding to and fusion with the egg oolemma, thus triggering the embryonic developmental program. The oviduct and the egg itself appear to coordinate sperm function to ensure that two functional competent gametes will meet, leading to fertilization. For the communication between sperm and somatic cells as well as between both gametes the information potential of carbohydrates is utilized, and this event probably prepares the next level of interactions, e.g., capacitation, acrosome reaction, egg binding, and fusion. The current perspective focuses on the role of molecules possibly implicated in sperm-oviduct and sperm-egg interactions. J. Exp. Zool. (Mol. Dev. Evol.) 285:259-266, 1999.

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PubMed1996

Isolation and characterization of a novel cytokinesis-deficient mutant in Dictyostelium discoideum.

Cytokinesis is a dramatic event in the life of any cell during which numerous mechanisms must coordinate the legitimate and complete mechanical separation into two daughter cells. We have used Dictyostelium discoideum as a model system to study this highly orchestrated event through genetic analysis. Transformants were generated using a method of insertional mutagenesis known as restriction enzyme-mediated integration (REMI) and subsequently screened for defects in cytokinesis. Mutants isolated in a similar screen suffered a disruption in the myosin II heavy chain gene, a protein known to be essential for cytokinesis and in a novel gene encoding a rho-like protein termed racE [Larochelle et al., 1996]. In the screen reported here we isolated a third type of mutant, called 10BH2, which also had a complete defect in cytokinesis. 10BH2 mutant cells are able to propagate on tissue culture plates by fragmenting into smaller cells by a process known as traction-mediated cytofission. However, when grown in suspension culture, 10BH2 cells fail to divide and become large and multinucleate. Phenotypic characterization of the mutant cells showed that other cytoskeletal functions are preserved. The distribution of myosin and actin is identical to wild type cells. The cells can chemotax, phagocytose, cap crosslinked receptors, and contract normally. However, the 10BH2 mutants are unable to complete the Dictyostelium developmental program beyond the finger stage. The mutant cells contain functional genes for myosin II heavy and light chains and the racE gene. Thus, based on these findings, we conclude that 10BH2 represents a novel cytokinesis-deficient mutant.

Actins↗

PubMed1996

Association of rous sarcoma virus DNA with Xenopus laevis spermatozoa and its transfer to ova through fertilization.

Mature Xenopus laevis spermatozoa are capable of binding plasmid pAPrC carrying the complete Rous sarcoma virus (RSV) DNA. Each sperm cell associates, on an average, with 70-160 molecules of the plasmid DNA in a DNase resistant form, if the spermatozoa were exposed to the DNA at a concentration of 1.0-1.4 micrograms/10(7) sperm cells. Fertilization with pAPrC-treated spermatozoa induced developmental malformations in 25-30% of embryos. Immunohistochemical analysis of tissue sections from defective animals revealed aberrations in myotomal structures, and increased expression of pp60src protein in myoblasts, neuronal tube, and epidermis. The presence of characteristic v-src and RSV-long terminal repeat (LTR) sequences in X. laevis DNA was detected by PCR analysis. Embryonic RNA hybridized with a src-specific and an RSV-LTR specific probes indicating expression of the viral DNA. Plasmid DNAs without the v-src gene (pATV9) or completely free of any RSV sequences (pBR322) did not induce any changes in embryonic development. Our results provide evidence that the pBR322-cloned DNA form of the RSV genome associates with frog sperm cells in a DNase-resistant manner suggesting internalization and may be subsequently carried into eggs during the process of artificial fertilization. Correlation between the defective morphogenesis of X. laevis and increased expression of the src gene as well as an interference of RSV DNA with the developmental programs of frog embryos are discussed.

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PubMed1998

Development of transgenic Xenopus laevis with a high C-src gene expression.

Xenopus laevis larvae with an elevated expression of c-src were generated by mating a transgenic X. laevis male frog carrying proviral Rous sarcoma virus (RSV) long terminal repeat (LTR) and most of the pol gene sequences in its sperm DNA and a normal X. laevis female frog. Offspring (15-20%) with a higher dosage of c-Src, detected in disorganized myotomal musculature and in cerebral and spinal neuronal cells by immunohistochemical analysis, developed abnormally, with edemas (in most cases), head deformities, and eye and axial system defects. In the remaining embryos, a small increase in c-src expression seemed to be compatible with normal embryogenesis. The dosage of c-Src correlated with the dosage of RSV LTR integrated in frog DNA as revealed by Southern and polymerase chain reaction (PCR) analyses. Authenticity of the integrated RSV LTR including enhancer sequence was proved by sequencing. Probing of total RNA from aberrant larvae demonstrated several times higher dosage of c-src mRNA in their tissues than in control tadpoles. We hypothesize that the integrated RSV regulatory sequences can stimulate the expression of c-src proto-oncogene of X. laevis above a threshold that interferes with the early developmental program of frog embryos.

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PubMed1996

Catecholamine metabolism and in vitro induction of premature cuticle melanization in wild type and pigmentation mutants of Drosophila melanogaster.

The major pathway leading to adult cuticle melanization in Drosophila melanogaster has been investigated by a combination of biochemical and genetic approaches. By comparing catecholamine pools in newly emerged flies and in frass (excreta) collected 1 to 4 days after eclosion from wild type with those obtained from several pigmentation mutants, the major flow of catecholamines through the pathway to an unidentified final catabolite was determined. We also demonstrate that incubation with dopamine in vitro induces premature melanization in wild type unpigmented pharate adults several hours before the developmentally programmed onset of melanization, supporting the hypothesis that the availability of catecholamines may be the limiting factor determining the onset of melanization and that the major enzymatic activities that act downstream of dopa decarboxylase in the pathway are deposited into the cuticle before pigmentation begins. In vitro melanization studies with various pigmentation mutants that are associated with critical enzymatic steps in Drosophila catecholamine metabolism are consistent with their proposed function and suggest a central role of N-beta-alanyldopamine in adult cuticle pigmentation.

Alleles↗

PubMed1996

Altered hexamerin regulation in prepupal Trichoplusia ni pseudoparasitized by Chelonus sp. near curvimaculatus.

Adult female wasps of species in the subfamily Cheloninae inject an egg, venom, polydnavirus and other materials into the host egg during oviposition. Hosts then exhibit precocious expression of the metamorphic developmental program, but then further development by the precocious prepupa is suppressed. These effects occur in truly parasitized hosts (those that contain a live endoparasite larva) as well as in pseudoparasitized hosts (that do not contain a live endoparasite). We report here that during the precocious prepupal stage, the hexamerins BJHSP1 and BJHSP2 persist in the hemolymph of pseudoparasitized hosts, whereas in normal larvae these proteins are cleared from the hemolymph in response to the normal surge in prepupal ecdysteroids. Northern blot analysis of poly(A) RNA showed that the basis for this persistence is not an abnormally high abundance of the transcripts on the day following wandering in pseudoparasitized larvae. Nor is the source of the hexamerins the parasite larva, for it is missing from the pseudoparasitized hosts. The hypothesis that the persistence is due to a suppressed titer of ecdysteroids in pseudoparasitized hosts (reported earlier: [jones et al., Arch Insect Biochem Physiol 21:155 (1992)] was tested by use of a large size variant of pseudoparasitized hosts in which the prepupal ecdysteroid titer is partially restored by endogenous ecdysteroid production. In such pseudoparasitized prepupae, the two hexamerins were cleared from the hemolymph on the day following host wandering behavior, as in normal larvae. Thus, the regulatory basis of the persistence of the hexamerins BJHSP1 and BJHSP2 in the hemolymph of pseudoparasitized hosts appears to be at the posttranslational level, with suppression of the prepupal ecdysteroid titer causing omission of the normal trigger for fat body uptake of the hexamerins.

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PubMed1999

Genetic variation in trophectoderm function in parthenogenetic mouse embryos.

The developing oocyte constitutes the source of a unique and essential molecular legacy that supports embryo metabolism for a substantial period after fertilization and that also directs important epigenetic events that prepare the embryonic genome for transcription and faithful execution of the developmental program. Parthenogenetically activated embryos provide a useful tool with which to examine how maternally derived factors contribute to early development. They also provide a means for evaluating genetic effects on the maternal genomic imprinting process. We report here that the genetic background of the oocyte affects trophectoderm function at the blastocyst stage. Parthenogenetic embryos obtained from activated (B6D2)F1 oocytes hatch efficiently in culture, whereas parthenogenones from C57BL/6 oocytes hatch less efficiently. Fertilized embryos of both strains hatch efficiently. The (B6D2)F1 parthenogenones also undergo blastocoel re-expansion after treatment with cytoskeletal inhibitors more rapidly than do C57BL/6 parthenogenones and exhibit a moderately greater abundance of the Na+, K(+)-ATPase alpha 1 subunit mRNA. Surprisingly, parthenogenones of both strains undergo blastocoel re-expansion more rapidly than do their normal fertilized counterparts. Parthenogenones of both types are able to attach efficiently in culture after removal of the zona pellucida. These observations indicate that significant genetic effects of maternal genotype on trophectoderm function are revealed in the absence of a paternal genetic contribution and that trophectoderm function also differs between parthenogenetic embryos and fertilized embryos. The differences observed between parthenogenetic and fertilized embryos indicate a likely role for one or more imprinted genes in the development of hatching and blastocoel expansion ability. The effect of maternal genotype on parthenogenetic embryo phenotype is consistent with possible differences in maternal genome imprinting or differences in ooplasm composition that have long-term effects on development. The specific differences in hatching and blastocoel re-expansion between parthenogenones of the two strains may be the result of differences in the activity or expression of a hatching enzyme or other molecules that affect fluid accumulation within the blastocyst, such as components of junctional complexes or proteins that regulate Na+, K(+)-ATPase activity.

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PubMedDate not supplied

Preconceptual caffeine exposure increases glucose utilization and accelerates development in the preimplantation rat embryo.

The present study was designed to investigate whether caffeine administered daily throughout the estrous cycle prior to fertilization affected the development of the subsequent preimplantation day 5 rat embryo. The viability parameters chosen for assessment were glucose utilization, cell number, and stage of embryonic development (morula to hatched blastocyst). Two independently replicated experiments were conducted. Together these experiments demonstrated that after fertilization, a proportion of affected oocytes maturing in a caffeine-perfused ovarian environment used and oxidised glucose at a significantly higher rate and were significantly more advanced developmentally compared with their litter mates or with the control counterparts. Cell number per embryo and the number of embryos recovered (litter size) remained constant, suggesting that caffeine, at the doses used, is unlikely to affect the ovulation rate or prevent fertilization. This study is significant because it demonstrates for the first time that a drug such as caffeine, when administered prior to ovulation and genomic activation, causes a quantitative difference in growth promoting energy utilization in a proportion of susceptible embryos after genome activation. A link between genomic imprinting and changed developmental program in the preimplantation embryos was suggested.

Animals↗

PubMed1998

Mucin and proteoglycan functions in embryo implantation.

Embryo implantation is a complex series of events that involves changes in pattern of expression of embryonic as well as uterine cell surface components. In the case of the embryo, these changes are driven by the developmental program. In the case of the uterus, these changes are triggered by both maternal hormonal influences as well as embryo-derived factors. Aspects of the implantation process vary among species; however, interaction between the external surface of the embryonic trophectoderm and the apical surface of the lumenal uterine epithelium is a common event. Progress is being made in defining the molecular players in these cell surface interactions. Large-molecular-weight mucin glycoproteins such as MUC1 are present at the apical surface of the uterine epithelium under most conditions. Under most circumstances, these mucins appear to protect the mucosal surface from infection and the action of degradative enzymes. These mucins are antiadhesive and also appear to represent a barrier to embryo attachment. Consistent with this model, reduction of mucin expression is observed in uterine lumenal epithelia in many species. Nonetheless, mucin expression persists in the human uterus during the proposed receptive phase. It is possible that mucin loss is localized to implantation sites in humans. Alternatively, mucins may function differently within the context of human implantation than in other species. Studies primarily performed in mice indicate that heparan sulfate proteoglycans, in particular, perlecan, appears on the exterior trophectodermal surface coincident with the acquisition of attachment competence. Various in vitro studies indicate that heparan sulfate proteoglycans support embryo attachment activity that may represent an early event in embryo-uterine interaction. Uterine epithelia cells express several complementary heparan sulfate-binding proteins that may participate in these attachment processes. Use of molecular genetic approaches in mouse models, as well as careful studies of the expression and function of these molecules in the context of implantation in various species are beginning to shed light on the key molecular events of implantation.

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PubMed2000

Rearrangement of chromatin domains in cancer and development.

Both the accomplishment of developmental programs and neoplastic transformation are linked to changes in the long-range organization of chromatin, in particular, DNA loop domains. The development of new methods that allow the study of interactions between the bases of DNA loops and the proteins of the nuclear matrix will help our understanding of the molecular mechanisms in such changes. These methods should also allow the establishment of a fingerprint "signature" for many cancers that may serve for diagnostic purposes. J. Cell. Biochem. Suppl. 35:54-60, 2000.

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PubMed2001

Characterization of the execution pathway of developing motoneurons deprived of trophic support.

Avian spinal motoneurons have been well characterized with regard to developmental programmed cell death (PCD). Approximately 50% of the neurons originally generated undergo cell death as they innervate their target muscles, and target derived trophic support plays an important role in regulating survival of these neurons. To investigate events mediating motoneuron PCD, we have examined the role of Bcl-2 family proteins, cytochrome C, and caspase-9 in this process. We report that while protein levels of Bcl-2, Bcl-xL, and Bax do not change within motoneurons as they become committed to die, a translocation of Bax from the cytosol to organelle membranes and the nucleus occurs coincident with the time when motoneurons become committed to cell death. In addition, cytochrome C is released from mitochondria to the cytosol in dying cells prior to the activation of caspases. Consequently, an enhanced caspase-9-like activity was detected in dying cells, and this activity was upstream and necessary for the appearance of a caspase-3-like activity. These results allow us to further define some of the critical events that mediate the execution phase of motoneuron death following trophic factor deprivation.

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PubMed1985

Development of mouse embryos in hanging drop culture.

Mouse blastocysts were cultured in hanging drops for up to 6 days in order to study development under conditions that avoid the distortion of embryos typically seen when they are allowed to attach to a glass or plastic surface. The survival rate of embryos in hanging drops was equal to that of embryos attached to culture dishes and superior to that of embryos suspended in gyrating flasks. Development of the embryonic portion was similar to that in vivo and on culture dishes but slower than in vivo; the egg cylinder stage was reached after 8-10 equivalent gestation days (4 to 6 days in culture), while that stage is reached at 5.5 to 6 days in vivo. The trophectoderm, however, developed in a unique manner. The cells migrated away from the inner cell mass (ICM), similar to embryos on a culture dish, but without a surface on which to spread they clustered distal to the ICM. In vivo, trophectoderm remained covering the ICM. By 5 days in hanging drop culture the embryos had developed a segmented appearance with trophoblast giant cells at the abembryonic pole, extraembryonic cells not covered by vacuolated endoderm in the central region, and embryonic endoderm surrounding a developing proamniotic cavity in embryonic ectoderm at the embryonic pole. These observations suggest that the trophectoderm is able to follow a developmental program independent of that in the embryonic portion and that its behavior is dominated by the different adhesive properties of the trophoblastic and embryonic cells.

Animals↗

PubMed1992

Selectivity in storage hexamerin clearing demonstrated with hemolymph transfusions between Hyalophora cecropia and Actias luna.

When Hyalophora cecropia hemolymph was injected into wandering Actias luna larvae, a methionine-rich hexamerin was selectively transferred to the host's fat body, and completely cleared from the hemolymph by the time of pupal eclosion. Donor arylphorin was 30-40% removed from the hemolymph, and riboflavin-binding hexamerin was even less completely cleared. During the pupal-adult molt, these rates were reversed: methionine-rich hexamerin disappeared no faster than bovine serum albumin, while riboflavin-binding hexamerin was rapidly and completely cleared from the hemolymph, even though A. luna hemolymph lacks a homologue of this protein; arylphorin, again, was cleared at an intermediate rate. Selective clearing of the three hexamerins occurred at similar stages in H. cecropia, their species of origin. Developmentally programmed clearing, with selectivity at least partially conserved between genera, was also demonstrated with transfused vitellogenin: in A. luna females that were forming yolk, H. cecropia vitellogenin was cleared more rapidly than bovine serum albumin; but in younger females, and in males at all stages of metamorphosis, this Mr 510,000 molecule was instead an indicator of nonselective, large protein clearing. Nonselective clearing was more complete during adult development than during pupation. It also showed signs of being more effective for small than for large proteins, insensitive to carbohydrate conjugates, and unsaturated at the protein levels used.

Animals↗

PubMed2001

Can molecular mechanisms of biological processes be extracted from expression profiles? Case study: endothelial contribution to tumor-induced angiogenesis.

Whereas the genome contains all potential developmental programs, expression profiles permit the determination of genes that are actively transcribed under defined physiological conditions. In this article, the idea of extracting biological mechanisms from expression data is tested. Molecular processes of the endothelial contribution to angiogenesis are derived from recently published expression profiles. The analysis reveals the sensitivity limits of experimental detection of transcriptional changes and how sequence-analytic techniques can help to identify the function of genes in question. We conclude that the transcripts (http://mendel.imp.univie.ac.at/SEQUENCES/TEMS/) found to be up-regulated in angiogenesis are involved in extracellular matrix remodeling, cellular migration, adhesion, cell-cell communication rather than in angiogenesis initiation or integrative control. Comparison with tissue-specific patterns of EST occurrence shows that, indeed, the presumptive tumor-specific endothelial markers are more generally expressed by cell types involved in migration and matrix remodeling processes. This exemplary study demonstrates how bioinformatics approaches can be helpful in deriving mechanistic information from diverse sources of experimental data.

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PubMed2003

Intercalary heterochromatin and genetic silencing.

We focus here on the intercalary heterochromatin (IH) of Drosophila melanogaster and, in particular, its molecular properties. In the polytene chromosomes of Drosophila, IH is represented by a reproducible set of dense bands scattered along the euchromatic arms. IH contains mainly unique DNA sequences, and shares certain features with other heterochromatin types such as pericentric, telomeric, and PEV-induced heterochromatin, the inactive mammalian X-chromosome and the heterochromatized male chromosome set in coccids. These features are transcriptional silencing, chromatin compactness, late DNA replication, underrreplication or elimination in somatic cells, and formation of the heterochromatin state in early embryogenesis. Post-translational modification of histones and the specific nonhistone protein complexes are shown to participate in the establishment and maintenance of silencing for all heterochromatin types. Many IH regions contain binding sites for HP1 and/or Pc-G proteins and all the regions are sites of heterochromatin-associated SuUR protein. Some IH regions are known to contain homeotic genes. Summarizing these data, we suggest that IH regions comprise stable inactivated genes, whose silencing is developmentally programmed.

Animals↗

PubMed2005

Memory mechanisms of active transcription during cell division.

The developmental programs of eukaryotic organisms involve the programmed transcription of genes. A characteristic gene expression pattern is established and preserved in each different cell type. Therefore, gene activation at a particular time and its maintenance during cell division are significant for cellular differentiation and individual development. Although many studies have sought to explain the molecular mechanisms of gene expression regulation, the mechanism through which gene expression states are inherited during cell division has not been fully elucidated yet. This review illustrates the general principles and the complexities involved in the establishment and maintenance of active transcription through cell cycles. It focuses on the most-recent findings about the ways in which molecular memory marks for active transcription are coordinated with cell cycle events, such as replication, mitosis and nuclear organization, to mediate transcription memory across cell division events, which may establish a unifying memory process of active transcription.

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