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PubMed1989

Management of extremity soft-tissue sarcoma.

Soft-tissue sarcomas remain relatively uncommon neoplasms, but they present major problems for both the patient and clinician. The identification of prognostic variables based on both clinical and histologic factors has allowed comparisons to be made between various therapeutic regimens. In extremity sarcoma, a more conservative operation utilizing adjuvant radiotherapy has decreased the need for radical surgery and maximized function without loss of survival benefit. The identification of high-risk groups, that is, patients with high-grade, large lesions, has highlighted the inadequacies of treatment in some areas. Similarly, this has led to more aggressive and innovative developmental programs. The progress, understanding, and therapeutic management of extremity lesions have not been matched in visceral and retroperitoneal tumors. Current efforts are directed at more appropriate use of radical surgery, maximizing conservative function-sparing operations with the use of adjuvant local therapy, and development of new regimens directed at prevention and treatment of metastatic disease.

Humans↗

PubMed1990

Nerve growth factor enhances neurite arborization of adult sensory neurons; a study in single-cell culture.

Nerve growth factor (NGF) is a well-established trophic factor of sympathetic and sensory neurons during development. NGF is, however, little known to be required for the maintenance or regulation of differentiated phenotypes of matured peripheral neurons. Since trophic factors, including NGF, are currently known to be secreted by non-neuronal cells, like Schwann cells and fibroblasts, a highly pure-neuron culture is required to assess the direct action of trophic factors on neurons. We have developed a single-neuron culture from neonatal and adult rat dorsal root ganglia in serum-free conditions, and estimated the primary effect of NGF on the morphological geometry of sensory neurons. We found that NGF promoted the neurite length of neonatal sensory neurons, rather than promoting arborization (branching of neurites), while in adult matured neurons NGF significantly enhanced neurite arborizations, rather than the maximal neurite extension, distance from the cell soma to the maximum margin of the territory of neurite extension. Total neurite length, the summed length of all neurites per neuron was significantly increased by NGF in both neonatal and adult neurons. NGF also increased the size of neuronal soma independent of neuronal maturation. Neonatal sensory neurons tended to die in 1 week despite the presence of NGF. In contrast, some adult sensory neurons were alive for more than 2 weeks in the absence of NGF. These results indicate that NGF more than simply accelerates a pre-existing developmental program in the matured stage, and that the promotion of neurite arborization by NGF in adult sensory neurons suggests that NGF may have some role in peripheral nerve regeneration via promotion of axonal sprouting.

Aging↗

PubMed1993

Delayed detyrosination of alpha-tubulin from parallel fibre axons and its correlation with impaired synaptogenesis in hypothyroid rat cerebellum.

The biochemical basis of retarded differentiation and maturation of microtubules and impaired synaptogenesis in hypothyroidism has been investigated by studying the temporal and spatial relationship between alpha-tubulin detyrosination in the parallel fibre axons of rat cerebellum and alterations in the activity of the detyrosinating enzyme, TTCP (tubulinyl tyrosine carboxypeptidase) with the progress of synaptogenesis in the molecular layer. Detyrosination was monitored by following the disappearance of stain from cerebellar sections, immunocytochemically labeled with a monoclonal antibody (20C6) specific for alpha-tubulin, tyrosinated at the C-terminal end. With respect to normal controls, detyrosination of alpha-tubulin from the parallel fibres of the molecular layer during synaptogenesis was not only delayed by about 5 days but also prolonged in the hypothyroid cerebellum. Correspondingly, the increase of TTCP activity in the developing thyroid deficient cerebellum was also delayed by about 1 week. Comparison of the developmental profile of TTCP activity in the normal and hypothyroid cerebellum during synaptogenesis revealed that the overall activity of the enzyme in the thyroid deficient cerebellum was reduced to almost half of that of the normal controls. These results establish that thyroid hormones are essential for the induction of TTCP, which catalyses detyrosination during the normal ontogenic development of rat cerebellum. Since our data also suggest that detyrosination precedes synaptic contacts to generate a class of differentiated microtubules functionally competent for synaptogenesis, the delayed detyrosination in the hypothyroid cerebellum may desynchronize the normal developmental program resulting in incomplete synaptogenesis.

Aging↗

PubMed1983

Differential regulation of duplicate alcohol dehydrogenase genes in Drosophila mojavensis.

These studies report the existence of multiple forms of alcohol dehydrogenase in extracts of Drosophila mojavensis. The existence of these forms can be best explained by the hypothesis of a duplication for the Adh locus in D. mojavensis. Electrophoretic variants at each locus have been identified and crosses between individuals carrying alternative alleles at each locus result in F1 progeny with six bands of ADH. This pattern is consistent with these individuals being heterozygous at two loci. The loci have been named Adh-1 and Adh-2. Examination of the isozyme content during development shows that the two Adh genes are not coordinately controlled but have separate developmental programs. In embryos and first and second instar larvae only Adh-1 is expressed. At about the time of the second molt Adh-2 expression commences in some of the same cells that previously expressed and continue to express Adh-1. This is evidenced by the existence of an interlocus heterodimer in third instar larvae. Both genes are expressed throughout pupation. Shortly after emergence Adh-1 expression declines. In mature males only ADH-2 is present. In mature females both Adh-1 and Adh-2 are expressed but not in the same cells since the interlocus heterodimer is absent. Examination of specific tissues reveals that most of the larval ADH is found in fat body cells and as in most tissues of third instar larvae both Adh-1 and Adh-2 are expressed. The single exception appears to be larval gut which contains ADH-1 but little if any ADH-2. In mature males and female flies all ADH containing tissues have only ADH-2. However, mature ovaries contain substantial quantities of ADH-1 which is apparently deposited into eggs. Given the extensive amount of available information on the Adh gene-enzyme system of D. melanogaster and the tools that can be applied to the analysis of homologous systems, the ADH duplication of D. mojavensis, and its regulation may be a useful one for studying differential gene regulation in specific cell types.

Alcohol Dehydrogenase↗

PubMed1983

Developmental regulation of myelin basic protein expression in mouse brain.

Developmental regulation of myelin basic protein expression in mouse brain has been examined by comparing the myelin basic protein coding potential of mRNA in vitro with the accumulation of myelin basic protein-related polypeptides in vivo. In vitro translation of mRNA isolated from mouse brain generated eight myelin basic protein-related polypeptides with apparent molecular weights of 34K, 30K, 29K, 26K, 21.5K, 18.5K, 17K, and 14K. A similar set of eight myelin basic protein-related polypeptides with corresponding molecular weights was identified in vivo when total brain proteins were analyzed by immunoblotting. Each of the myelin basic protein-related polypeptides shows a characteristic developmental profile in terms of mRNA level and rate of accumulation implying a complex developmental program of myelin basic protein gene expression with regulation and modulation at several different biosynthetic levels.

Aging↗

PubMed1983

Effects of dexamethasone and 5-bromodeoxyuridine on protein synthesis and secretion during in vitro pancreatic development.

Protein synthesis and secretion during in vitro pancreatic development and after treatment with the glucocorticoid dexamethasone and the thymidine analog 5-bromodeoxyuridine (BrdU) was monitored using two-dimensional gel electrophoresis. At 14 days gestation, the synthesis of more than 200 proteins and the secretion of a complex set of proteins was detected. The relative rate of synthesis and secretion of the majority of this set of proteins decreased dramatically during development; after 6 days of culture most were no longer detected. In contrast, the synthesis and secretion of pancreas-specific exocrine proteins amylase, a Sepharose binding protein (protein 2), and chymotrypsinogen first detected after one day in culture, increased throughout the 6-day culture period. Other pancreatic digestive (pro)enzymes normally found in the adult such as the basic form of chymotrypsinogen, lipase, ribonuclease, and trypsinogen were not detected during the culture period. Thus at least two distinct regulatory events are involved in the expression of the exocrine genes during development. Dexamethasone treatment during the 6-day culture period selectively increased the synthesis of amylase and several other minor secretory proteins. BrdU treatment caused major changes in the protein synthetic and secretory patterns of the pancreas as well as in morphogenesis. BrdU treated pancreases showed greatly reduced synthesis of amylase, protein 2, and chymotrypsinogen and prolonged synthesis of many proteins normally detected only at early stages of pancreatic development. BrdU treatment also stimulated the secretion of a set of proteins ostensibly associated with duct cells. Thus, BrdU specifically alters the developmental program of the pancreas.

Age Factors↗

PubMed1986

The developmental regulation of single-cell motility in Dictyostelium discoideum.

The velocity of single amebae in the absence of a chemotactic signal has been analyzed during growth, development, rapid recapitulation, and dedifferentiation in the cellular slime mold Dictyostelium discoideum. It is demonstrated that (1) the velocity of axenically grown cells in half that of bacterially grown cells, (2) the velocity of bacterially grown cells decreased to roughly the same low level as axenically grown cells approximately 5 hr after the removal of exogeneous bacteria, (3) the velocity remains low for a 7-hr period preceding the onset of aggregation in both axenically and bacterially grown cells, (4) the velocity increases transiently at the onset of aggregation for both axenically and bacterially grown cells, (5) the velocity decreases to a very low level after the formation of loose aggregates and remains at that level at least through the early culminate I stage, (6) the velocity is not stimulated in 13-hr developing cells (finger stage) by inducing rapid recapitulation, (7) the velocity decreases after the erasure event in cultures of 7-hr developing cells (ripple stage) stimulated to undergo dedifferentiation, but the inhibition of the erasure event by the addition of 10(-4) M cAMP does not block this decrease. These results demonstrate that the basal level of single-cell motility in growing cultures is significantly influenced by the nutrient composition of the supporting medium, and that the transient increase in single-cell motility at the onset of aggregation is under the rigid control of the initial developmental program. Both rapid recapitulation and the program of dedifferentiation appear to have no influence on the basal level of single-cell motility.

Cell Differentiation↗

PubMed1986

Replication and expression of an X-linked cluster of Drosophila chorion genes.

Two 80- to 100-kb chromosomal replicons containing clustered chorion genes amplify in the ovarian follicle cells during the final 22 hr of Drosophila oogenesis. We have studied the relationship between amplification and transcription within one of these domains, located at 7E10-7F3,4 on the X chromosome. A tandem cluster of six genes, encoding chorion structural proteins s36-1, s38-1, and four putative minor chorion protein mRNAs, was mapped in the central 18 kb of the amplified domain, a region showing the highest levels of amplification. The regions both proximal and distal to this gene cluster, where lower levels of amplification occur, were also transcribed in ovary, but mRNAs produced specifically during choriogenesis were not detected. Thus, differences in amplification do not appear to modulate differential RNA accumulation. Instead, the gradient of amplification observed in egg chamber DNA may simply reflect the mechanism of amplification. In the female sterile mutation, In(1)ocelliless, a chromosomal rearrangement separates the central gene cluster into two parts, only one of which retains the capacity to amplify. Genes located within the unamplified portion of the ocelliless chromosome were expressed at the appropriate time during oogenesis, but at a 5- to 10-fold reduced level of RNA per gene. Thus neither cluster integrity nor amplification are required for the normal developmental program of gene expression within the cluster.

Animals↗

PubMed1987

Distribution of fiber types in embryonic chick limb muscles innervated by foreign motoneurons.

The differentiation of distinct myotube fiber types in chick limb muscle development is coincident with innervation. The role of motoneurons in influencing fiber type differentiation was analyzed by causing chick hind limb muscles to be innervated by inappropriate motoneurons and then examining experimental muscles for changes in the distribution of myosin ATPase fiber types. Motoneuron innervation of limb muscles was altered by performing either limb shifts, limb reversals, or large spinal cord reversals on early neural tube or limb bud stage chick embryos. The distribution of fiber types was then analyzed in muscles from stage 36 (E10) to stage 45 (E20) embryos after processing hind limb sections for myosin ATPase histochemistry. In the majority of experimental muscles examined (267/312), the distribution of myosin ATPase fiber types was unaltered. In the remaining experimental muscles (14%), alterations in the distribution of myosin ATPase fiber types occurred, indicating that in some cases, foreign innervation may alter the developmental program of differentiating myotubes. The results suggest that myotubes differentiate myosin ATPase staining characteristics according to an intrinsic program and that these differentiating myotubes are selectively innervated by motoneurons of the appropriate type under most conditions including normal development. Under exceptional circumstances of motoneuron-muscle fiber type mismatch, embryonic motoneurons can alter fiber type expression.

Adenosine Triphosphatases↗

PubMed1988

Cell lineage conversion in the sea urchin embryo.

The mesoderm of the sea urchin embryo conventionally is divided into two populations of cells; the primary mesenchyme cells (PMCs), which produce the larval skeleton, and the secondary mesenchyme cells (SMCs), which differentiate into a variety of cell types but do not participate in skeletogenesis. In this study we examine the morphogenesis of embryos from which the PMCs have been removed microsurgically. We confirm the observation of Fukushi (1962) that embryos lacking PMCs form a complete skeleton, although in a delayed fashion. We demonstrate by microsurgical and cell marking experiments that the appearance of skeletogenic cells in such PMC-deficient embryos is due exclusively to the conversion of other cells to the PMC phenotype. Time-lapse video recordings of PMC-deficient embryos indicate that the converting cells are a subpopulation of late-ingressing SMCs. The conversion of these cells to the skeletogenic phenotype is accompanied by their de novo expression of cell surface determinants normally unique to PMCs, as shown by binding of wheat germ agglutinin and a PMC-specific monoclonal antibody. Cell transplantation and cell marking experiments have been carried out to determine the number of SMCs that convert when intermediate numbers of PMCs are present in the embryo. These experiments indicate that the number of converting SMCs is inversely proportional to the number of PMCs in the blastocoel. In addition, they show that PMCs and converted SMCs cooperate to produce a skeleton that is correct in both size and configuration. This regulatory system should shed light on the nature of cell-cell interactions that control cell differentiation and on the way in which evolutionary processes modify developmental programs.

Animals↗

PubMed1988

Immunofluorescence assessment of the timing of appearance and cellular distribution of Na/K-ATPase during mouse embryogenesis.

We have employed immunofluorescence with a rat kidney Na+/K+-ATPase polyclonal antibody to investigate the cellular distribution and timing of appearance of this enzyme during preimplantation development. The enzyme is first detected in the late morula within the cytoplasm of each blastomere. When cavitation begins this distribution changes dramatically to a ring encircling the blastocoel, restricted to the basolateral cell margins. Using this enzyme as a marker for cavitation, we examined its expression in embryos that had been treated with wheat germ agglutinin (WGA), which causes cleavage arrest and was reported to trigger premature compaction- and cavitation-like events in early cleavage stages (L. V. Johnson, 1986, Dev. Biol. 113, 1-9). Although WGA-treated 2-,4-, and 8-cell embryos quickly underwent compaction- and cavitation-like events, no Na+/K+-ATPase expression was observed. Thus the WGA effect does not likely involve acceleration of the developmental program for cavitation. Embryos arrested at the 8-cell stage but cultured overnight to Day 4, however, expressed the enzyme in the typical blastocyst pattern (around each fluid-filled cavity). We conclude that Na+/K+-ATPase expression is initiated or increases dramatically in the late morula and is independent of cytokinesis. The enzyme assumes a distribution during cavitation consistent with its presumed role in transtrophectodermal fluid transport.

Animals↗

PubMed1988

Myosin heavy chain expression during development and following denervation of fast fibers in the red strip of the chicken pectoralis.

The myosin heavy chain composition of muscle fibers that comprise the red strip of the pectoralis major was determined at different stages of development and following adult denervation. Using a library of characterized monoclonal antibodies we found that slow fibers of the red strip do not react with antibodies to any of the fast myosin heavy chains of the superficial pectoralis. Immunocytochemical analysis of the fast fibers of the adult red strip revealed that they contain the embryonic fast myosin heavy chain rather than the adult pectoral isoform found throughout the adult white pectoralis. This was confirmed using immunoblot analysis of myosin heavy chain peptide maps. We show that during development of the red strip both neonatal and adult myosin heavy chains appear transiently, but then disappear during maturation. Furthermore, while the fibers of the superficial pectoralis reexpress the neonatal isoform as a result of denervation, the fibers of the red strip reexpress the adult isoform. Our data demonstrate a new developmental program of fast myosin heavy chain expression in the chicken and suggest that the heterogeneity of myosin heavy chain expression in adult fast fibers results from repression of specific isoforms by innervation.

Age Factors↗

PubMed1988

Collagens support embryo attachment and outgrowth in vitro: effects of the Arg-Gly-Asp sequence.

Collagen types I through VI support attachment and outgrowth of mouse blastocysts in vitro. We found that embryos acquire the ability to attach to collagens type II and VI relatively early in their developmental program. The time at which half of the embryos displayed outgrowth formation and the morphology of outgrowths formed on these two collagen types are similar to those observed for laminin, fibronectin, and hyaluronate. Embryos acquire the ability to outgrow on the other collagen types at a later time in culture. Both "native" and denatured collagens support embryo attachment and outgrowth, indicating that this activity is intrinsic to the primary collagens' structure. A synthetic peptide containing the sequence Arg-Gly-Asp inhibits embryo outgrowth on collagen type II and denatured collagen type IV, whereas a peptide containing the related sequence, Arg-Gly-Glu, has relatively little effect on embryo outgrowth. In contrast, embryo attachment to collagen types I, V, and VI was not inhibited specifically by the Arg-Gly-Asp peptide sequence. Consequently, it appears that embryos use multiple adhesion systems to attach to collagens. Among these are adhesion systems that have a peptide recognition specificity similar to that of fibronectin receptors. These studies indicate that embryo interactions with collagens may be one aspect of the tissue invasion processes that take place during implantation.

Amino Acid Sequence↗

PubMed1988

Changes in myosin and C-protein isoforms proceed independently of the conversion to singly innervated neuromuscular junctions in developing pectoral muscle.

Changes in contractile protein expression during myogenesis are usually categorized as developmentally programmed or neuronally dependent. Studies on aneurogenic chick embryos indicated that the neuronally dependent phase begins at about Embryonic Day 15, immediately prior to the fetal transition in myosin and C-protein expression. The prime candidate for the neuronal event that induces the fetal transition is the conversion to the adult form of singly innervated neuromuscular junctions (NMJs), which occurs contemporaneously with the fetal transition. Using curare to inhibit the conversion to focal innervation, we find that the fetal transition proceeds unimpaired, demonstrating that there is no causal link between the fetal transition and the conversion to focal innervation. Furthermore, because the doses of curare used inhibit motor activity by more than 80%, the fetal transition can occur in the absence of normal levels of motor activity. These observations show that the fetal transition in ovo is not induced by either a specific change in innervation or use. Rather, the dependence on innervation seems to be a consequence of the need for muscle activity to prevent atrophy, and the fetal transition appears to have characteristics more like the preprogrammed contractile protein transitions that precede it.

Acetylcholinesterase↗

PubMed1989

Evidence for expression of a common myosin heavy chain phenotype in future fast and slow skeletal muscle during initial stages of avian embryogenesis.

We have utilized a key biochemical determinant of muscle fiber type, myosin isoform expression, to investigate the initial developmental program of future fast and slow skeletal muscle fibers. We examined myosin heavy chain (HC) phenotype from the onset of myogenesis in the limb bud muscle masses of the chick embryo through the differentiation of individual fast and slow muscle masses, as well as in newly formed myotubes generated in adult muscle by weight overload. Myosin HC isoform expression was analyzed by immunofluorescence localization with a battery of anti-myosin antibodies and by electrophoretic separation with SDS-PAGE. Results showed that the initial myosin phenotype in all skeletal muscle cells formed during the embryonic period (until at least 8 days in ovo) consisted of expression of a myosin HC which shares antigenic and electrophoretic migratory properties with ventricular myosin and a distinct myosin HC which shares antigenic and electrophoretic migratory properties with fast skeletal isomyosin. Similar results were observed in newly formed myotubes in adult muscle. Future fast and slow muscle fibers could only be discriminated from each other in developing limb bud muscles by the onset of expression of slow skeletal myosin HC at 6 days in ovo. Slow skeletal myosin HC was expressed only in myotubes which became slow fibers. These findings suggest that the initial commitment of skeletal muscle progenitor cells is to a common skeletal muscle lineage and that commitment to a fiber-specific lineage may not occur until after localization of myogenic cells in appropriate premuscle masses. Thus, the process of localization, or events which occur soon thereafter, may be involved in determining fiber type.

Animals↗

PubMed1989

Regulation of nerve growth factor mRNA levels in developing rat heart ventricle is not altered by sympathectomy.

The survival of sympathetic and sensory neurons is known to be controlled by nerve growth factor (NGF) supplied by the targets of innervation, yet little is known about how target NGF synthesis is regulated. We have investigated the pattern of NGF mRNA expression in developing rat heart ventricle using a sensitive RNA blotting procedure. We find that the concentration of NGF mRNA increases steadily from Embryonic Day 17 to peak levels at 10-14 days postnatal and then declines about twofold and stabilizes at the level found in adults. The rise in NGF mRNA concentration correlates with the arrival and differentiation of sympathetic nerve terminals in the heart and the cessation of sympathetic cell death. To assess the role of innervating sympathetic neurons in regulating NGF mRNA expression, neonatal rats were sympathectomized by treatment with 6-hydroxydopamine and heart ventricles were assayed for NGF message. Although this treatment reduced ventricle norepinephrine content by 82%, no significant change in NGF mRNA concentration was observed. These results suggest that the developmental program of NGF mRNA production in the heart is not influenced by innervating sympathetic neurons.

Aging↗

PubMed1989

Drosophila embryonic neuroblasts in culture: autonomous differentiation of specific neurotransmitters.

Isolated neuroblasts from gastrula-stage Drosophila embryos divide and differentiate in vitro to produce clonally derived clusters of neurons. Both serotonin and dopamine are expressed within these cultures in patterns that are similar to their distributions in vivo. Clusters containing serotonergic neurons are generally distinct from those with dopaminergic neurons, suggesting that different neuroblasts produce neurons with these phenotypes. The appearance of each transmitter correlates with transcription of dopa decarboxylase in the transmitter-positive cells. The developmental program leading to the appearance of either serotonergic or dopaminergic neurons is different for each transmitter type. Thus, serotonergic cells are progeny of early neuroblast divisions, whereas dopaminergics arise throughout the lineage. Inhibition of cell division, but not nuclear division, with cytochalasin B demonstrates that the expression of the serotonin phenotype requires a determined number of DNA replications. These experiments establish that neuroblasts, as soon as they are formed during early gastrulation events in Drosophila, are already determined for the subsequent expression of transmitter phenotype.

Animals↗

PubMed1989

Localization of epidermal growth factor precursor in tooth and lung during embryonic mouse development.

The murine epidermal growth factor (EGF) precursor is a 1217 amino acid protein which contains mature EGF (amino acid residues 977-1029) as well as eight EGF-like repeats. Although the highest levels of EGF are found in the adult male mouse submandibular gland, the results of in situ hybridization studies and mRNA analyses suggest that EGF precursor mRNA is synthesized in several adult mouse tissues including the lung and the incisor. To determine if EGF precursor gene expression is intrinsic to the developmental program for either embryonic tooth or lung organogenesis, sense and antisense oligodeoxyribonucleotide probes corresponding to amino acids 1070-1081 of the precursor were used to localize cellular sites of synthesis of EGF precursor mRNA by in situ hybridization. Antibodies directed against amino acid residues 348-691 of the precursor were used in immunodetection techniques to identify either EGF precursor protein or processed derivatives. In contrast to earlier reports indicating that embryonic mouse tissues do not synthesize EGF precursor mRNA, we found that EGF precursor mRNA is present in clusters of ectoderm-, mesoderm-, and ectomesenchyme-derived cells associated with embryonic teeth and lung organs. Moreover, epitopes common to the EGF precursor were immunolocalized in both the epithelial and mesenchymal tissues of embryonic mouse tooth and lung organs. These results suggest that the EGF precursor and/or motifs contained within the precursor molecule, including mature EGF, may play an instructive or permissive role in epithelial-mesenchymal interactions pursuant to organogenesis.

Aging↗