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PubMed2006

Getting infectious: formation and maturation of Plasmodium sporozoites in the Anopheles vector.

Research on Plasmodium sporozoite biology aims at understanding the developmental program steering the formation of mature infectious sporozoites - the transmission stage of the malaria parasite. The recent identification of genes that are vital for sporozoite egress from oocysts and subsequent targeting and transmigration of the mosquito salivary glands allows the identification of mosquito factors required for life cycle completion. Mature sporozoites appear to be equipped with the entire molecular repertoire for successful transmission and subsequent initiation of liver stage development. Innovative malaria intervention strategies that target the early, non-pathogenic phases of the life cycle will crucially depend on our insights into sporozoite biology and the underlying molecular mechanisms that lead the parasite from the mosquito midgut to the liver.

Animals↗

PubMed1981

Effects of altered thyroid states on myelinogenesis.

Myelinogenesis was studied in controls and in rats treated since birth with Methimazole (hypothyroid) or thyroxine (hyperthyroid). The amount of myelin in forebrain and its protein composition were determined between 13 and 40 days of age, the period of most rapid myelin accumulation. Hypothyroid rats had reduced on both and brain weights relative to controls and the yield of myelin was reduced on both a per brain and a per milligram brain protein basis. Developmental changes in the protein composition of isolated myelin followed the pattern of control animals (the percentage of total myelin protein present as proteolipid protein, large basic protein, and small basic protein increased, as did the ratio of proteolipid/large basic protein) but were delayed temporally by 1-2 days. Hyperthyroid rats also had reduced body and brain weights. At 13 days myelin accumulation was greater than that of controls, corresponding to an earlier initiation of myelination. At later ages myelin yield was reduced on a per brain basis but not on a per milligram brain protein basis. The developmental pattern of myelin protein composition was accelerated temporally by 1-2 days. Myelination in optic nerve, assayed by proteolipid protein content, also was slightly delayed in hypothyroid animals and somewhat accelerated in hyperthyroid animals. The relative synthesis of myelin proteins (determined as incorporation of intracranially injected [(3)H]glycine into myelin protein relative to incorporation into whole brain protein), as well as distribution of radioactivity among individual myelin proteins, was determined. The results supported the conclusion of the myelin protein accumulation study; hypothyroidism retards the developmental program for myelinogenesis, whereas in the hyperthyroid state myelin synthesis is initiated earlier but is also terminated earlier.

Animals↗

PubMed1990

Evidence for delta-opioid binding and GTP-regulatory proteins in 5-day-old rat brain membranes.

The availability of the bispenicillamine enkephalin [3H] [D-Pen2,D-Pen5]enkephalin ([3H]DPDPE) a highly selective ligand for delta-opioid receptors, has made possible a more definitive examination of the ontogeny of this receptor subtype. In this report, the binding characteristics of [3H]DPDPE in 5-day-old neonatal (P-5) and adult rat brain are compared. Analysis of saturation curves as well as homologous displacement data revealed no significant difference in the binding affinity of [3H]DPDPE between P-5 animals and adults. Conversely, the binding capacity increased fivefold during this period. The delta-specificity of the sites was further proven by competition experiments with mu- and delta-selective ligands. Mn2+ (0.5 mM) elevated [3H]DPDPE specific binding by lowering the Kd, whereas 50 microM 5'-guanylylimidodiphosphate inhibited it by decreasing the total number of high-affinity binding sites in both P-5 animals and adults. Pertussis toxin-catalyzed ADP ribosylation experiments revealed the presence of 40-kDa proteins, with a molecular mass corresponding to G protein subunits alpha i/alpha o, as early as 1 h after birth. There was a low, but detectable, basal low-Km GTPase activity in P-5 animals, which increased fivefold during postnatal development. The present report establishes the existence of high-affinity [3H]DPDPE binding as well as GTP-regulatory proteins 5 days after birth. Yet, heterologous competition studies and ionic effects suggest that neonatal binding sites differ from adult receptors. Whether the neonatal sites are newly synthesized, incompletely processed sites or a developmentally programmed isoform remains to be determined.

Animals↗

PubMed2006

Down-regulation of drebrin A expression suppresses synaptic targeting of NMDA receptors in developing hippocampal neurones.

Drebrin is a major F-actin-binding protein in the brain. We have recently demonstrated that drebrin A (neurone-specific isoform) clusters at synapses and governs targeting of the post-synaptic density 95 protein to synapses during development. To determine the role of drebrin A on excitatory synapse formation, we analysed whether the suppression of drebrin A expression affects filopodia-spine morphology and synaptic targeting of NMDA receptors in cultured hippocampal neurones. Suppression of developmentally programmed up-regulation of drebrin A by antisense treatment significantly decreased the density and width of filopodia-spines. Immunocytochemistry showed that the antisense treatment did not attenuate synaptic clustering of NMDA receptors under conditions that permitted spontaneous activities but inhibited the accelerated targeting of NMDA receptors into synapses by its antagonist D-(-)-2-amino-5-phosphonopentanoic acid. These results indicate that drebrin A up-regulation plays a pivotal role in spine morphogenesis and activity-dependent synaptic targeting of NMDA receptors.

Cells, Cultured↗

PubMedDate not supplied

Stage- and tissue-specific patterns of cell division in embryonic and larval tissues of amphioxus during normal development.

The distribution of dividing cells is described for embryos and larvae of amphioxus (Branchiostoma floridae) pulse labeled with bromodeoxyuridine. Because cell division is assessed for all of the developing tissues, this is the first comprehensive study of developmental cell proliferation for an animal lacking a stereotyped cell lineage. In amphioxus, cell divisions are virtually synchronous during cleavage, but become asynchronous at the blastula stage. Starting at the neurula stage, after the origin of the mesoderm, the proportion of dividing cells progressively declines in the somitic mesoderm and notochord. Other tissues, however, deviate from this pattern. For example, in the mid-neurula, there is a brief, intense burst of mitosis at the anterior end of the neural plate. Also, from the neurula through the early larval stage, all of the ectoderm cells cease dividing and develop cilia that propel the animal through the water; subsequently, in the epidermis of later larvae, mitosis resumes and the proportion of ciliated cells declines as muscular undulation gradually replaces ciliation for swimming. Finally, in the early larvae, there is a terminal arrest of cell division in three cell types that differentiate early to participate in feeding as soon as the mouth opens-namely the ciliated pharyngeal cells that produce the feeding current and the secretory cells of the club-shaped gland and endostyle that export food-trapping mucus into the pharynx. In sum, these stage- and tissue-specific changes in cell proliferation intensity illustrate how the requirements of embryonic and larval natural history can shape developmental programs.

Animals↗

PubMed2002

The GAD-given Right of Dentate Gyrus Granule Cells to Become GABAergic.

JANUS, THE ANCIENT ROMAN GOD OF GATES AND DOORS HAD TWO FACES: one looked into the past, and the other, into the future. Do neurons possess a Janus face when it comes to neurotransmitters, or a given neuron is to be forever solely gamma-aminobutyric acid (GABA) ergic, glutamatergic, dopaminergic, peptidergic, or YOURPREFERREDTRANSMITTERergic? The answer is that the terminals of many neurons are homes to even more than two neurotransmitters. All this in spite of the "one neuron-one transmitter" usual misinterpretation of Sir Henry Hallett Dale's postulate, originally meant to indicate that a metabolic process taking place in the cell body can influence all processes of the same neuron. A large variety of neurons in the CNS, many of them GABAergic, produce and release chemicals that satisfy some of the criteria used to define neurotransmitters. The usual scenario for a dual-transmitter terminal is that the fast-acting transmitter such as GABA or glutamate is stored in regular synaptic vesicles, whereas a neuropeptide is stored in dense core vesicles (1). The vesicular zinc found in many glutamatergic terminals also may be considered to be a second neurotransmitter, based on its vesicular packaging with the aid of a specific vesicular transporter, and its postsynaptic actions through high-affinity binding sites and permeation through certain channels (2). Whenever a "fast" and a "slow" neurotransmitter are present in the same presynaptic terminal, it is customary to assume that their release can be differentially regulated (1). There is little convincing experimental support for this phenomenon in the mammalian CNS. The coexistence of two "fast" neurotransmitters in the same terminal is less frequent, but not unheard of. In neonatal sympathetic neurons cocultured with cardiac myocytes, norepinephrine and acetylcholine coexist and have opposite actions on the cardiac muscle cells (3). Very recently we learned that brain-derived neurotrophic factor acting at the low-affinity neurotrophin receptor p75(NTR), perhaps as part of a programmed developmental switch, can convert the phenotype of the sympathetic neuron from noradrenergic to cholinergic (4). Other examples of two fast neurotransmitters released from the same neuron include GABA and glycine in interneurons of the spinal cord (5) and glutamate and dopamine in ventral midbrain dopamine neurons (6). Of all CNS neurons, the granule cells of the dentate gyrus appear to be the champions of neurotransmitter colocalization: glutamate, enkephalin, dynorphin, zinc, and finally GABA (2)(7)(8)(9). With this many transmitters in a single neuron, there are probably different ways in which they can be released. Dynorphin and other opioid peptides can be released directly from the dendrites to inhibit excitatory transmission (8). A similar mechanism may take place for GABA, as described in cortical GABAergic neurons (10).

Journal Article↗

PubMedDate not supplied

A cytogenetic study of development in mechanically disrupted pairs of Tetrahymena thermophila.

We examined the nuclear behavior of mating Tetrahymena cells that had been mechanically disrupted at various times throughout conjugation. Disruption was achieved by agitating conjugating Tetrahymena in the presence of 0.1-3 mm glass beads. Two minutes of agitation with 1 mm beads yielded optimal pair disruption (70%) with high viability (92%). Disrupting pairs between 0-4.7 h after the initiation of mating produced mostly disrupted conjugants in which development was aborted. However, as many as 20% of these early disrupted conjugants completed development even without their mating partners. After 5 h the percentage of disrupted conjugants completing development increased dramatically, reaching 80% by 6.7 h. These results support a model suggesting that events associated with nuclear exchange and fusion 5 h into conjugation trigger a commitment to completion of the postzygotic developmental program. The early conjugants that completed development following disruption suggest that development can be sustained even in the absence of a mating partner. This represents a novel method of bringing the micronuclear genome into macronuclear expression with minimal cytoplasmic exchange between partners. We discuss these results in light of a model relating cortical and nuclear signaling events that reciprocally drive conjugal development.

Animals↗

PubMed1989

Microbial lectin cofunction with lytic activities as a model for a general basic lectin role.

Lectins are ubiquitous proteins, which exhibit a specific and reversible sugar-binding activity. They react with glycosylated macromolecules and cells and may coaggragate them and lead to their lysis or alterations. Various lectin biological effects are well known, but their basic biological function is considered as yet unknown. In the present review, an experimental evidence and theoretical considerations are forwarded for supporting our suggestion that the general basic lectin or lectinoid (lectin-like protein) function in microorganisms, plants and animals is a cofunction enabling the activities of key lytic enzymes (lysins: glycosidases, proteases, esterases, phosphatases, hemolysin, etc.). The lectin service is: homing onto glycosylated receptors, anchoring to them and induction of cooperative conformational effects which enable their counterpart lysin activity on exogenous or endogenous target molecules and cells. The 'lectin-lysin' pair may reside in the same molecule, or in linked subunits. It may also be formed by cofunction of two separate entities originating from one or two (homogenous or heterogenous) cell sources. The lectin and lysin may be free or cell-bound components located intra or extracellularly. The final result of their cofunction is practically irreversible; either cell and macro-molecule lysis for nutrition, homeostasis and protection or cell alteration, reorganization and new productivity. Our suggestion emphasizes the prominent analogy of lectins to lytic enzyme positioning sites (LEPS), immunoglobulins and polypeptide hormones. The lectin analogy to LEPS and immunoglobulins is exhibited in the lectin-dependent cell and macromolecule lysis for nutritional and homeostatic purposes or for protection, respectively. The hormone-like lectin activity is exhibited in the lectin-dependent cell alterations. In addition to similar functions and effects, the analogy also includes the properties and behavior of these proteins. The suggested hypothesis is based on experimental evidence from microorganisms, plants and animals. It envisions the lectin and lectinoid function in cell attacks on glycosylated molecules or cells, cell-substratum and cell-cell interactions (fusion, invasion, etc.), cell transformation and formation of special structures. All of them according to a developmental program, or special (especially unfavourable) environmental conditions. The lectin resistance to proteolysis and unfavourable pH or temperature is in accord with the suggested hypothesis.

Animals↗

PubMed1997

Trehalases and trehalose hydrolysis in fungi.

The simultaneous presence of two different trehalose-hydrolysing activities has been recognised in several fungal species. While these enzymes, known as acid and neutral trehalases, share a strict specificity for trehalose, they are nevertheless rather different in subcellular localisation and in several biochemical and regulatory properties. The function of these apparently redundant activities in the same cell was not completely understood until recently. Biochemical and genetic studies now suggest that these enzymes may have specialised and exclusive roles in fungal cells. It is thought that neutral trehalases mobilise cytosolic trehalose, under the control of developmental programs, chemical and nutrient signals, or stress responses. On the other hand, acid trehalases appear not to mobilise cytosolic trehalose, but to act as 'carbon scavenger' hydrolases enabling cells to utilise exogenous trehalose as a carbon source, under the control of carbon catabolic regulatory circuits. Although much needs to be learned about the molecular identity of trehalases, it seems that in fungi at least one class of acid trehalases evolved independently from the other trehalases.

Fermentation↗

PubMed1995

Multiple initiation mechanisms adapt phage T4 DNA replication to physiological changes during T4's development.

We summarize the evidence for multiple pathways to initiate phage T4 DNA replication. In any infecting chromosome, leading DNA strands can be primed from pre-replicative transcripts, independent of primase activity, at one of several origins. Within each origin region, there are multiple RNA-DNA transition sites. However, the priming potential at each single site is very low. Our results suggest that origin transcripts can become primers for leading strand DNA synthesis without being processed, but that a promoter-proximal segment of each origin transcript plays an important structural role, as a proposed wedge, in the transition from RNA to DNA synthesis. Two recombination-dependent pathways render subsequent phage T4 DNA replication independent of transcription. The first of these requires proteins that are synthesized during the pre-replicative phase of infection. It is active as soon as the first growing points, initiated at origins, have reached a chromosomal end. The other one requires at least one late protein: endonuclease VII, a resolvase that cuts recombinational junctions. The latter pathway can bypass primase deficiencies by allowing retrograde DNA synthesis without Okazaki pieces. We discuss the integration of these multiple and redundant pathways into the developmental program of T4. Competition between these initiation mechanisms and with other DNA transactions allows for integration of replication controls with transcription, recombination and packaging of the DNA.

Bacteriophage T4↗

PubMed1991

Transplantation of normal and leukemic human bone marrow into immune-deficient mice: development of animal models for human hematopoiesis.

The successful engraftment of human hematopoietic cells into immune-deficient mice offers a novel approach to characterize the developmental program of human hematopoiesis. While it is not yet possible to achieve high-level engraftment of all human lineages, several methods have been developed to successfully engraft human lymphoid cells and reconstitute partial immune function. In addition to mature cell types, there is evidence that progenitors and perhaps stem cells can engraft the murine bone marrow. Recent work suggests that provision of exogenous human cytokines significantly increases the level of human cell engraftment and stimulates the development of multiple lineages. Progress has also been made to establish animal models of human hematopoietic diseases such as leukemia, autoimmunity, and infectious diseases.

Animals↗

PubMed1993

The role of thymic epithelium in the establishment of transplantation tolerance.

From experimental observations on induction of transplantation tolerance, we discuss a model that accounts for tissue-specific tolerance to antigens not expressed inside the thymus. It is postulated that antigens presented to differentiating T cells by thymic epithelium (or at large within the thymic environment) positively select and activate self-reactive T cells. A developmental program and/or prevalent conditions in the thymic environment restrict the proliferative potential and the class of effector functions that can be exerted by differentiating T cells activated in the thymus. These do not mediate inflammatory or cytolytic activities, but instead will produce the appropriate mediators to inhibit aggressive effector activities by other T cells activated in their proximity. Such "regulatory" functions will be locally expressed at the periphery upon recognition of tissue antigens shared with the thymus, towards newly formed thymic emigrants directed at tissue-specific antigens expressed by the same "target" cells. This mechanism imposes "dominant tolerance", based on specific self-recognition and predominantly established in the embryonic and neonatal period. Throughout life, the process of thymic positive selection results in all newly-formed T cells being susceptible to such suppressive mechanisms, but becoming increasingly refractory with time in the resting, post-differentiative stage. Absence of antigen (nonself) in the embryonic and neonatal life therefore allows for the accumulation of such "suppression-resistant" antigen-reactive T cells that will mount aggressive responses upon antigenic exposure. Tolerance or immunity thus represent two classes of specific immune responses, the relative predominance of which is determined by the frequency of each type of effector T cell, representing the antigenic overlap between thymic and peripheral tissues, as well as the frequency of tissue-specific T-cell generation, and the kinetics of peripheral antigenic exposure. Tolerance induced by hemopoietic cells to all other tissues is also "dominant" and based on thymic colonization and persistence of antigenic cells, with the consequent positive selection of regulatory T cells and peripheral conditions for the establishment of suppression. Upon this simple model, that ensures "interclonal class regulation" by "bridging" regulatory and effector T cells through the recognition of different antigens on the same target cell, other mechanisms which are based on V-region interactions among T cells (Ben-Nun et al. 1981, Pereira et al. 1989, Webb & Sprent 1990, Gaur et al. 1993) might well operate to ensure "dominant tolerance" by self-reactivity and class regulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1998

Mesectoderm is a major target of retinoic acid action.

The RAR and RXR families of retinoid nuclear receptors each comprise three isotypes (alpha, beta and gamma). In vitro, RARs bind to their cognate DNA response elements as heterodimers with RXRs. Null mutations of all six isotypes have been generated. The defects displayed by RAR alpha, beta and gamma single null mutant mice are confined to a small subset of the tissues normally expressing these receptors. This discrepancy reflects the existence of a functional redundancy, since RAR double null mutants exhibit congenital malformations in almost every organ system. In particular, most of the structures derived from the mesectoderm are severely affected. Analysis of mutant mice lacking both RARs and RXRs indicates that RXR alpha:RAR gamma heterodimers are instrumental in the patterning of craniofacial skeletal elements, whereas RXR alpha:RAR alpha heterodimers may be preferentially involved in the generation of neural crest cell-derived arterial smooth muscle cells. Both RXR alpha:RAR beta and RXR alpha:RAR gamma heterodimers appear to function during the development of the ocular mesenchyme. Moreover, atavistic reptilian cranial structures are generated in RAR mutants, suggesting that the RA signal has been implicated in the modification of developmental programs in the mesectoderm during evolution.

Abnormalities, Multiple↗

PubMed1998

Cellular plasticity among axolotl neural crest-derived pigment cell lineages.

Many of the factors and mechanisms guiding the migration/differentiation of neural crest cells that give rise to a number of distinguishable cell types, including all dermal and epidermal pigment cells, remain unknown. The axolotl possesses three pigment cell types that differentiate according to specific developmentally programmed sequences and contribute to pigment pattern in the adult. A single lineage of the crest that becomes restricted to one of three pigment cell types gives us the opportunity to examine the existence of a neural crest stem cell population and the potential for trans-differentiation events. Interpretations of experiments involving drug-treated and mutant axolotls implicate cellular plasticity leading to observed phenotypes. We present results from recent in vitro studies designed to identify parameters influencing differentiation events of individual neural crest-derived pigment cell lineages. We demonstrate that the differentiation of xanthophores is enhanced, while that of the melanophores are inhibited in guanosine-supplemented neural crest cell cultures. Data suggest that the increase in one pigment cell population is at the expense of another, indicative of cellular plasticity. Videomicroscopy used in this study agrees with an abundance of correlative evidence supporting the hypothesis of transdifferentiation events among neural crest-derived pigment cell populations. The embryonic neural crest-derived pigment cell system is an ideal model to study differentiation of multipotential stem cells that play critical roles in patterning.

Ambystoma↗

PubMed2002

Chromosome analysis of blastocysts cultured under the diabetic condition.

Chromosomes of Slc:ICR mouse blastocysts cultured under the diabetic condition were analyzed to clarify the effect of glucose and ketone body (DL-beta-hydroxybutyric acid). In the group exposed to glucose plus ketone body or glucose alone, blastocysts showed higher incidences of chromosome abnormalities, especially numerical abnormalities such as aneuploidy and polyploidy, than in the control group (p < 0.01). The association of nucleolus organizing regions was increased in the blastocysts exposed to glucose plus ketone body, which seems to be related to the increase in numerical abnormalities. Structural abnormalities such as break and fragment were also observed, but there was no significant difference between the diabetic and nondiabetic conditions. These results from chromosome analysis of the cultured blastocysts suggest that the diabetic condition may directly cause chromosome abnormalities in early embryos, especially aneuploidies, and may thus induce duplications or deletions of genes. These chromosomal damages may disrupt the developmental programs for organogenesis and may be involved in diabetes-induced teratogenesis.

3-Hydroxybutyric Acid↗

PubMed1989

The molecular control of normal and leukemic hematopoiesis: myeloid cells as a model system.

The establishment of a cell culture system for the clonal development of hematopoietic cells has made it possible to identify the proteins that control growth and differentiation of different hematopoietic cell lineages and to discover the molecular basis of normal and abnormal cell development in blood-forming tissues. A model system with myeloid cells has shown that normal hematopoietic cells require different proteins to induce cell multiplication and cell differentiation and that a cascade of interactions between proteins determines the correct balance between immature and mature cells in normal development. Gene cloning has shown that there is a family of different genes for these proteins. Normal protein regulators of hematopoiesis can control the abnormal growth of certain types of leukemic cells and suppress malignancy by inducing differentiation to mature non-dividing cells, and there are different pathways of inducing differentiation. Results from studies on the molecular control of growth and differentiation in normal myeloid hematopoietic cells, on changes in the normal developmental program, and on the suppression of malignancy in myeloid leukemia have shown that (a) malignancy can be suppressed by inducing differentiation either with or without genetic changes in the malignant cells, (b) this suppression of malignancy does not have to restore all the normal controls, and (c) genetic abnormalities that give rise to malignancy, which include changes in homeobox genes, can be bypassed and their effects nullified by inducing differentiation that stops cells from multiplying.

Bone Marrow↗

PubMed1992

Aging in the T lymphocyte compartment. A developmental view.

A decline in the capacity of bone marrow cells to differentiate to T lymphocytes was found when cells from young and old donors were seeded onto an alymphoid fetal thymus. A step-by-step analysis of cell-cell interactions of the lymphohemopoietic cells and the thymic stroma indicated an effect of age on a variety of cell differentiation parameters. These included a decrease in the affinity of bone marrow cells to the stroma, and in their capacity to compete with the thymic lymphoid resident cells on colonization of the thymus. There was a significant decrease in the ability of cells of old donors to replicate sequentially within the thymic microenvironment. There was a reduced capacity of bone marrow cells from aging mice to express a developmental preference after seeding onto a syngeneic fetal thymus in a mixture with cells from allogeneic donors. We addressed the question whether the aging thymus contains increased levels of immature cells that fail to differentiate in the involuted thymic microenvironment by seeding thymocytes from young and old donors onto the fetal thymic stroma. The values of T cells that developed from the old donor inoculum were lower under these conditions. Our studies suggest that at least some of the manifestations of aging in the T cell compartment are related to developmentally programmed events in the lymphohemopoietic cell compartment.

Aging↗

PubMed1999

Cellular mechanisms of risk and transformation.

Our early work using the first array and imaging methods for the quantitative analysis of the expression of 4000 cDNA sequences suggested that modulation of mitochondrial gene expression was a factor in determining whether colonic epithelial cells displayed a differentiated or transformed phenotype. We have since dissected a pathway in which mitochondrial function is a key element in determining the probability of cells undergoing cell-cycle arrest, lineage-specific differentiation, and cell death. Moreover, this pathway is linked to signaling through beta-catenin-Tcf, but in a manner that is independent of effects of the APC gene on beta-catenin-Tcf activity. Utilization of unique mouse genetic models of intestinal tumorigenesis has confirmed that mitochondrial function is an important element in generation of apoptotic cells in the colon in vivo and has demonstrated that modulation of cell death may be involved in intestinal tumor progression rather than initiation. Normal spatial and temporal patterns of cell proliferation, differentiation, and apoptosis in the colonic mucosa are determined by developmentally programmed genetic signals and external signals generated by homo- and heterotypic cell interactions, humoral agents, and lumenal contents. Mitochondrial function may play a pivotal role in integrating these signals and in determining probability of cells entering different maturation pathways. How this is accomplished is under investigation using high-density cDNA microarrays.

Animals↗