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PubMed1996

Nerve growth factor withdrawal induces the apoptotic death of developing septal cholinergic neurons in vitro: protection by cyclic AMP analogue and high potassium.

Nerve growth factor regulates the developmental programmed cell death of certain neurons in the peripheral nervous system. The functions of nerve growth factor in the central nervous system are less well characterized. Nerve growth factor withdrawal results in the protein synthesis-dependent death of a large percentage of developing septal cholinergic neurons in sandwich tissue culture. In this study double labelling techniques were used to demonstrate that septal cholinergic neurons subjected to nerve growth factor withdrawal exhibit condensed chromatin and fragmented nuclei, and are labelled intensely for fragmented DNA. These degenerative changes are characteristic of apoptotic cell death. Half of the cholinergic neurons were committed to die and could no longer be rescued by nerve growth factor reapplication following approximately 16.5 h of nerve growth factor deprivation, whereas half of the cholinergic neurons could no longer be rescued by cycloheximide addition after only 9 h of nerve growth factor deprivation, suggesting that nerve growth factor and cycloheximide effect rescue by distinct mechanisms. Addition of a cyclic AMP analogue or depolarization with high K+, but not the general nuclease inhibitor aurintricarboxylic acid, prevented the death of cultured septal cholinergic neurons subjected to nerve growth factor withdrawal. Furthermore, these agents are capable of rescuing cholinergic neurons subjected to a period of nerve growth factor withdrawal after which addition of cycloheximide is no longer protective. Thus, nerve growth factor, cyclic AMP and high K+ can effect rescue after inhibition of translation ceases to be protective. These findings suggest that under defined conditions in vitro, withdrawal of nerve growth factor from septal cholinergic neurons during a critical period of development results in the apoptotic death of these CNS neurons, which can be prevented at the post-translational level by nerve growth factor, cyclic AMP and high K+.

Animals↗

PubMed1992

Age-dependent alterations of synaptic performance and plasticity in crustacean motor systems.

Age-related changes in synaptic performance and plasticity are surveyed in crustacean neuromuscular systems. These systems are functionally differentiated into phasic and tonic types, with different attributes of synaptic function and plasticity. Conversion of phasic neuromuscular junctions to a more phasic phenotype can be brought about by altering the activity of selected neurons. This type of plasticity disappears in older animals in some motor neurons, but is retained in others. Developmental programs set constraints on the age-dependent modifications of plasticity. Crustacean motor neurons are often characterized by great longevity, with progressive addition of new branches and synapses to keep up with growth of innervated muscle cells. Certain age-related compensatory mechanisms found in neuromuscular junctions of other species may not be required in crustaceans.

Aging↗

PubMed1988

A morphological and biochemical study of the myelin-like membrane structures formed in cultures of pure oligodendrocytes.

This study reports the production of myelin-like membranes in oligodendrocyte subcultures derived from 20-day-old primary glial cell cultures of newborn rat brain. These multi-layered structures show a variable number of membrane turns; up to 10 concentric lamellae are found in 3- to 4-week-old subcultures. When they are compacted, alternate dense and intraperiodic lines with a periodicity of 11.2 nm are noticeable. The most typical myelin proteins were detected straight on the multi-lammellar structures by a gold immunocytochemical method. Subcellular fractions containing these myelin-like structures were isolated by ultracentrifugation on a discontinuous sucrose gradient. They were analysed by sodium dodecylsulfate-polyacrylamide gel electrophoresis and immunoblotting; UDP-galactose: ceramide galactosyltransferase and 2',3'-cyclic nucleotide 3'-phosphohydrolase activities were also measured. The results indicate that the multi-layered membrane profiles have many characteristics of the myelin found in vivo; nevertheless some differences were still apparent. Our data support the concept of the cultured oligodendrocytes expressing the intrinsic myelinogenic properties and possessing a basic developmental program of myelination, apparently in the absence of stimuli coming from other brain cells.

Animals↗

PubMed1995

Hydroxy- and non-hydroxy-galactolipids in developing rat CNS.

Rat spinal cord (1-24 weeks postnatal) was analysed by HPLC for various species of galactolipids that accumulate in mammalian myelin during development. Cerebral tissue of the same animals was taken as reference. The levels of the major galactolipids, galactosylceramide (GalCer) and its sulfated analog (SGalCer), increased linearly during the first 2 months after birth. At 3 months, constant levels were reached that were approx. 4-fold (GalCer) and 2.5-fold (SGalCer) higher than in cerebral tissue of corresponding age. The accumulation of galactoglycerolipids slightly preceded that of galactosphingolipids. Levels of galacto-glycerolipids were much lower (4% of galactosphingolipids in 3-and 2.5% in 6-month-old spinal cord on weight basis) and decreased upon CNS maturation. During the first postnatal month, the ratio of non-hydroxy- over hydroxy-species (NFA/HFA) of cerebral GalCer declined from 2.2 to 0.5 whereas the NFA/HFA ratio for cerebral SGalCer increased from 1.0 to 1.8 in the same period. Through development the hydroxy-species contributed 56-60% to GalCer and 28-41% to SGalCer in spinal cord, whereas in cerebrum of 24-week-old rats 73% of GalCer and 48% of SGalCer was alpha-hydroxylated in the ceramide moiety. These data point to different developmental programs with respect to galactolipid metabolism of oligodendrocytes in high- (spinal cord) as compared to low-myelinated (cerebral) areas of rat CNS.

Animals↗

PubMed1988

Nucleotide sequence and expression of the human skeletal alpha-actin gene: evolution of functional regulatory domains.

Regulation of the actin multigene family involves the recognition of regulatory sequences that specify the tissue type and developmental program of expression for each actin isotype. In order to investigate the underlying regulatory mechanisms, the human skeletal alpha-actin gene and its 5' regulatory region have been cloned and sequenced. This actin gene has seven exons; there is one large intron in the 5' untranslated region which is characteristic of the actins and many muscle-specific genes. The 5' flanking sequences are sufficient to direct tissue-specific and differentiation-regulated expression when transfected into the heterologous rat L8 myogenic cells, indicating a highly conserved regulatory system. The DNA sequence was compared to that of other actin genes, and several regions of sequence similarity were identified, particularly within regions known to be important for gene expression. Most notable among the conserved sequences are the CC(A/T rich)6GG (CArG box) motifs which have demonstrated interactions with trans-acting transcriptional factors. This same motif has been identified in several other genes and in some also serves as a binding site for transcription regulatory factors.

Actins↗

PubMed1992

The identification and characterization of KRAB-domain-containing zinc finger proteins.

The zinc finger motif is a highly conserved tandemly repeated sequence of 28-30 amino acids that was first identified in transcription factor TFIIIA from Xenopus laevis. Subsequently, similar motifs were found and characterized in many genes from mammalian genomes and the genomes of lower eukaryotes such as Drosophila and yeast, thereby defining a large superfamily of genes. Non-finger-coding modules conserved among members of subfamilies of zinc finger genes have been described in the murine genome (finger-associated boxes, or FAX domain) and the human genome (Krüppel-associated boxes, or KRAB domain). Here we report the identification and partial characterization of more members of the human KRAB-containing subfamily of genes. Based on Southern blot hybridization experiments, they also are zinc-finger-coding genes. All members share a highly homologous 42-amino-acid-long A element of the described KRAB domain. The conservation extends to the murine developmentally expressed zinc finger gene, mKr2. The homologous sequences, however, are part of the 5'-untranslated region. In all cases for which there is adequate information, the KRAB domain is found at the NH2-terminus of the respective protein. In one zinc-finger-encoding cDNA clone that we characterized further in this work, BRc1744 (ZNF45), the KRAB domain most probably constitutes the entire second exon of the gene. Based on the data, it is tempting to speculate that the FAX- and KRAB-containing zinc finger genes define subfamilies of genes with overlapping functions that participate in the regulation of common or similar developmental programs.

Amino Acid Sequence↗

PubMed1992

Transforming growth factor-alpha gene expression in the hypothalamus is developmentally regulated and linked to sexual maturation.

Hypothalamic injury causes female sexual precocity by activating luteinizing hormone-releasing hormone (LHRH) neurons, which control sexual development. Transforming growth factor-alpha (TGF-alpha) has been implicated in this process, but its involvement in normal sexual maturation is unknown. The present study addresses this issue. TGF-alpha mRNA and protein were found mostly in astroglia, in regions of the hypothalamus concerned with LHRH control. Hypothalamic TGF-alpha mRNA levels increased at times when secretion of pituitary gonadotropins--an LHRH-dependent event--was elevated, particularly at the time of puberty. Gonadal steroids involved in the control of LHRH secretion increased TGF-alpha mRNA levels. Blockade of TGF-alpha action in the median eminence, a site of glial-LHRH nerve terminal association, delayed puberty. These results suggest that TGF-alpha of glial origin is a component of the developmental program by which the brain controls mammalian sexual maturation.

Animals↗

PubMed1990

The initiation of development at fertilization.

As seen, important advances have now been made in understanding the beginning of development at fertilization. Free calcium and pHi level changes result from a sperm-mediated breakdown of PPI with production of IP3. The resultant calcium increase, either alone or in concert with diacylglycerol, activates the Na(+)-H+ exchange and a consequent cytosolic pHi level increase. The calcium increase is responsible for the NADP change (via NAD kinase) and possibly the change in G6PD. These two changes could be involved solely in producing NADPH for fertilization membrane hardening or these changes could also have some role in the later initiation of DNA synthesis. The finding that other enzymes assayed in permeabilized cells also evince large changes in activity suggests that a global change may be occurring with important portents for cell activity. The role of calcium in furthering subsequent synthetic events, however, is unclear since no calcium target has yet been described that is necessary for the subsequent specific synthesis of proteins, as cyclins, or for the initiation of DNA synthesis. The pHi level increase, in concert with increased calcium, might be sufficient to start off protein synthesis and subsequent cyclin accumulation. However, the pHi level increase, independently of protein synthesis, can initiate new DNA synthesis. These independent events converge in the putative activation of MPF by cyclin, which then starts off the first mitotic cycle. Other independent events are associated with the sperm entry, cortical modifications, fertilization membrane elevation and the numerous changes leading to the fusion of the sperm and egg nucleus in the egg center. Fertilization represents one of the best studied examples of how a covert developmental program is made overt by an external messenger. The challenges for the near future are to explain how sperm-egg contact leads to PPI hydrolysis and how pHi level changes (and Cai level changes?) lead to the initiation of the cell cycle. The challenge for the distant future is describing how this program is set up during oogenesis.

Animals↗

PubMed1993

POU-domain proteins: structure and function of developmental regulators.

POU-domain proteins are a group of developmental regulators found in organisms as distant as worm and man. The sequence conservation of the POU-domain has allowed the characterization of increasing numbers of proteins containing the domain, many of which act to control the generation and maintenance of differentiated cell phenotypes in organs as diverse as skin and brain. Analysis of the means by which POU-domain proteins regulate transcription has led to a further understanding of how this group initiates specific developmental programs.

Animals↗

PubMed1993

Genetics, development and plant evolution.

The recent mapping of quantitative trait loci in plants indicates that traits are often controlled by relatively few genes, some of which have large effects. Developmental genetics has shown that plant development is often regulated by transcription factors that activate developmental programs in response to internal or environmental signals. These transcription factors are good candidates for the major genes that govern morphological evolution in plants.

Anthocyanins↗

PubMed1991

Immune-deficient mice as models for human hematopoietic disease.

The growth of human hematopoietic cells in immune-deficient mice promises to revolutionize our ability to study the normal developmental program of human hematopoiesis and the biological consequences of aberrant proliferation and differentiation. Advances in stem cell purification will require assays to test for function, and the identification and the characterization of novel hematopoietic growth factors will be aided by in vivo experiments. The engraftment of hematopoietic cells directly from patients with disease should ultimately lead to animal models for many human hemopathies and leukemias. Already important preliminary experiments have established the feasibility of such models for leukemia, cancer, infectious diseases, and autoimmunity. The production of human antibodies directed against toxic agents for which humans cannot be immunized could provide the basis for improved pharmaceuticals. Although an important foundation has been laid, much work remains to explore the full potential of this mouse transplantation system.

Animals↗

PubMed2004

Ubiquitin, proteasome and parkin.

The ubiquitin-proteasome system (UPS) is important for intracellular proteolysis, and is responsible for a diverse array of biologically important cellular processes, such as cell-cycle progression, signaling cascades and developmental programs. This system is also involved in the protein quality control, which maintains the health of the cell. Thus, the UPS provides a clue for understanding of the molecular mechanisms underlying various neurodegenerative diseases. In the last decade, we witnessed a tremendous progress in uncovering the mechanisms of Parkinson's disease (PD). Of the several genes that can cause familial PD, parkin, the causative gene of autosomal recessive juvenile parkinsonism (ARJP), is of a special interest because it encodes an ubiquitin-protein ligase, which covalently attaches ubiquitin to target proteins, designating them for destruction by the proteasome. This review summarizes recent studies on the UPS pathway with a special reference to parkin, focusing on how parkin is linked to the pathogenesis of ARJP.

Animals↗

PubMed2004

Molecular dissection of egg fertilization signaling with the aid of tyrosine kinase-specific inhibitor and activator strategies.

Fertilization is triggered by sperm-egg interaction and fusion that initiate a transient rise(s) in the free intracellular calcium ([Ca(2+)](i)) that is responsible for a series of biochemical and cell biological events, so-called "egg activation". Calcium-dependent egg activation leads to the initiation of developmental program that culminates in the birth of individuals. A growing body of knowledge has uncovered the molecular mechanisms underlying sperm-induced transient [Ca(2+)](i) increase(s) to some extent; namely, in most animals so far studied, a second messenger inositol 1,4,5-trisphosphate (IP(3)) seems to play a pivotal role in inducing [Ca(2+)](i) transient(s) at fertilization. However, signaling mechanisms used by sperm to initiate IP(3)-[Ca(2+)](i) transient pathway have not been elucidated. To approach this problem, we have employed African clawed frog, Xenopus laevis, as a model animal and conducted experiments designed specifically to determine the role of the Src family protein-tyrosine kinases (SFKs or Src family PTKs) in the sperm-induced egg activation. This review compiles information about the use of PTK-specific inhibitors and activators for analyzing signal transduction events in egg fertilization. Specifically, we focus on molecular identification of Xenopus Src and the signaling mechanism of the Src-dependent egg activation that has been established recently. We also summarize recent advances in understanding the role of the Src family kinases in egg fertilization of other model organisms, and discuss future directions of the field.

Animals↗

PubMed2005

Cyclooxygenase variants: the role of alternative splicing.

Alternative splicing of cellular pre-mRNA is responsible for production of multiple mRNAs from individual genes. Splice variants are expressed in cell- and tissue-specific contexts that are important in development and physiology. Alternative splicing can serve as a regulatory mechanism whereby developmental programming and environmental factors/stimuli affect biological activities of translated proteins. Cyclooxygenase (COX)-1 and -2 genes produce splice variants whose biological expression, relevance, and activities have been of significant interest. COX variants are produced by a variety of splicing mechanisms. Four structural domains of the COX proteins (the amino terminal signal peptide, membrane-binding domain, dimerization domain, and catalytic domain) are defined by specific COX exons. COX splice variants may, therefore, result in potential changes in protein subcellular localization, dimerization, and activity. COX variant proteins may act in roles which diverge from those of COX-1 and -2.

Alternative Splicing↗

PubMedDate not supplied

Hedgehog signaling and cell cycle control in differentiating erythroid progenitors.

Hedgehog (Hh) signaling regulates differentiation in numerous systems, but its functions in the control of hematopoietic differentiation have not been extensively explored. Initial studies have indicated that hedgehog signaling affects the proliferation and differentiation of erythroid progenitors (Detmer, K., et al., Erythroid differentiation in vitro is blocked by cyclopamine, an inhibitor of hedgehog signaling. Blood Cells Mol. Dis. 26(4) (2000) 360-372). To examine the effect of Hh signaling on the erythroid developmental program at the molecular level, Hh signaling in committed erythroid progenitors differentiating in vitro was inhibited, and the appearance/disappearance of molecular markers of erythroid differentiation was monitored. The expression timetable for CD34, CD36, the erythropoietin receptor, and glycophorin A was retarded in the absence of Hh signaling. Hemoglobinization was delayed and decreased relative to controls. Morphological changes of erythroid maturation were also delayed. The fraction of cells in S-phase was decreased during the initial period of exponential expansion as assessed by propidium iodide staining and flow cytometry, as was the rate of tritiated thymidine incorporation. A modest decrease in the proliferation rate was observed. These results suggest that Hh signaling is one of the mechanisms in the regulation of erythroid proliferation and differentiation.

Biomarkers↗

PubMedDate not supplied

Evolving beyond perfection: an investigation of the effects of long-term evolution on fractal gene regulatory networks.

This paper continues a theme of exploring algorithms based on principles of biological development for tasks such as pattern generation, machine learning and robot control. Previous work has investigated the use of genes expressed as fractal proteins to enable greater evolvability of gene regulatory networks (GRNs). Here, the evolution of such GRNs is investigated further to determine whether evolution exhibits natural tendencies towards efficiency and graceful degradation of developmental programs. Experiments where "perfect" GRNs are evolved for a further thousand generations without the addition of any further selection pressure, confirm this hypothesis. After further evolution, the perfect GRNs operate in a more efficient manner (using fewer proteins) and show an improved ability to function correctly with missing genes. When the algorithm is applied to applications (e.g. robot control) this equates to efficient and fault-tolerant controllers.

Algorithms↗

PubMed2006

The cAMP response element binding protein (CREB) as an integrative HUB selector in metazoans: clues from the hydra model system.

In eukaryotic cells, a multiplicity of extra-cellular signals can activate a unique signal transduction system that at the nuclear level will turn on a variety of target genes, eliciting thus diverse responses adapted to the initial signal. How distinct signals can converge on a unique signalling pathway that will nevertheless produce signal-specific responses provides a theoretical paradox that can be traced back early in evolution. In bilaterians, the CREB pathway connects diverse extra-cellular signals via cytoplasmic kinases to the CREB transcription factor and the CBP co-activator, regulating according to the context, cell survival, cell proliferation, cell differentiation, pro-apoptosis, long-term memory, hence achieving a "hub" function for cellular and developmental processes. In hydra, the CREB pathway is highly conserved and activated during early head regeneration through RSK-dependent CREB phosphorylation. We show here that the CREB transcription factor and the RSK kinase are co-expressed in all three hydra cell lineages including dividing interstitial stem cells, proliferating nematoblasts, proliferating spermatogonia and spermatocytes, differentiating and mature neurons as well as ectodermal and endodermal myoepithelial cells. In addition, CREB gene expression is specifically up-regulated during early regeneration and early budding. When the CREB function was chemically prevented, the early post-amputation induction of the HyBraI gene was no longer observed and head regeneration was stacked. Thus, in hydra, the CREB pathway appears already involved in multiple tasks, such as reactivation of developmental programs in an adult context, self-renewal of stem cells, proliferation of progenitors and neurogenesis. Consequently, the hub function played by the CREB pathway was established early in animal evolution and might have contributed to the formation of an efficient oral pole through the integration of the neurogenic and patterning functions.

Animals↗

PubMed2006

Neurotrophin-directed differentiation of human adult marrow stromal cells to dopaminergic-like neurons.

Marrow-isolated adult multilineage inducible (MIAMI) cells were differentiated in vitro to neuronal cells in a neurotrophin-dependent fashion. After induction, the cells revealed electrophysiological features similar to those observed in mature neurons. Primary early passage human MIAMI cells without any type of co-cultures with other cell types were used. The developmental program involved a multi-step process requiring the concerted action of brain-derived neurotrophic factor, nerve growth factor and depended on neurotrophin-3, after basic fibroblast growth factor withdrawal. MIAMI-derived neuron-like cells sequentially expressed the neuronal markers, developed a complex neurite outgrowth and arborization, and acquired electrophysiological characteristics similar to those observed in mature neurons. The young and old MIAMI-derived neuronal cells developed both inward and outward currents upon depolarization, similar to those observed in normal neurons. These results represent the earliest evidence that neurotrophin-3 can direct the differentiation of non-neural stem cells from human adult bone marrow stroma to neuron-like cells in vitro. Supplementing the aforementioned multi-step process with sonic hedgehog, fibroblast growth factor 8, and retinoic acid increased the expression of molecules involved in dopaminergic differentiation and of tyrosine hydroxylase, the rate limiting enzyme of dopamine synthesis. MIAMI cells from young and old individuals represent autologous human cell populations for the treatment of disorders of the skeletal and nervous systems and for applications in cell therapy and reparative medicine approaches.

Adolescent↗