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Expression dynamics and functional implications of DNA topoisomerase II beta in the brain.

Mammalian DNA topoisomerase II beta is a type II DNA topoisomerase that catalyses topological transformations of genomic DNA by the transport of one DNA double helix through another. The II beta enzyme is highly expressed in cells that have undergone the final cell division and committed to differentiate into neuronal cells. The II beta enzyme in the differentiating neuronal cells is located in the nucleoplasm and is actively engaged in its catalytic reaction in vivo. When enzyme action is interfered with a specific inhibitor in vitro, transcriptional induction of a subset of genes fails to occur during neuronal differentiation. Detailed analyses of developing rat cerebellum and the cerebrum of mice with disrupted II beta genes have revealed that DNA topoisomerase II beta is necessary for the developmentally regulated expression of certain genes in cells committed to a neuronal fate after the final division. Herein, we review a dynamic aspect of DNA topoisomerase II beta in the brain with special emphasis on developing cerebellar neurons.

Animals↗

Development of orientation discrimination in infancy.

It has previously been found by us, with a visual evoked potential (VEP) measure, that orientation discrimination of dynamic patterns in infants can be demonstrated from around 6 weeks after birth. Experiments are reported in which orientation discrimination was measured behaviourally, in two infant control habituation procedures, with both dynamic and static patterns. When dynamic patterns identical to those in our previous VEP studies were used, the first positive evidence of orientation discrimination was found at around 6 weeks postnatally. The time course of both the VEP and the behavioural measures was similar. However, with static patterns, evidence of orientation discrimination by newborns was found if the infants were allowed to compare the habituated and novel orientations in a paired simultaneous comparison after habituation, but was not found when the habituated and novel stimulus were presented sequentially. The positive evidence of orientation discrimination in newborns supports the hypothesis that some form of orientationally tuned detectors can be used for discrimination of static patterns at birth. However, some developmental change over several weeks seems to be required before a positive electrophysiological VEP response can be measured for dynamic patterns changing in orientation.

Child Development↗

Regulatory roles for mitochondria in the peri-implantation mouse blastocyst: possible origins and developmental significance of differential DeltaPsim.

Studies of mitochondria in mouse and human oocytes and preimplantation stage embryos have focused primarily on their metabolic capacity to generate ATP. However, it is becoming increasingly apparent that mitochondria are also regulatory agents in other processes involved in the establishment of developmental competence, including calcium homeostasis and apoptosis. The magnitude of the inner mitochondrial membrane potential, or its polarity (DeltaPsim), is a physiochemical property of mitochondria related to levels of organelle activity, and differences in the magnitude and spatial distribution of high- and low-polarized mitochondria have been suggested to influence oocyte and early embryo competence. Here, we investigated mitochondrial polarity in normal and diapausing peri-implantation-stage mouse blastocysts, and their corresponding outgrowths, for indications of cell-type-specific regulatory functions or activities in which these organelles may be engaged. The results demonstrate that cell-type- and location-specific domains of differential DeltaPsim exist in the peri-implantation blastocyst and remain unchanged during blastocyst outgrowth and during delayed implantation, which for the latter, is accompanied by the suppression of mitochondrial oxidative phosphorylation. Our findings demonstrate that cell-type-specific DeltaPsim in the peri-implantation blastocyst is not an intrinsic property of the corresponding mitochondria but one that can be mediated by the dynamics of intercellular contact. Cells with high- or low-polarized mitochondria are differentially affected by photosensitization, with developmental consequences related to embryo behavior and outgrowth performance. Differences in polarity are discussed with respect to the participation of mitochondria in regulatory and morphogenetic processes in the normal peri-implantation embryo. The persistence of high DeltaPsim in the diapausing embryo is suggested to be associated with the regulation of levels of cytoplasmic free calcium and the ability of the embryo to reactivate development when delayed implantation terminates.

Adenosine Triphosphate↗

A dynamic switch in the replication timing of key regulator genes in embryonic stem cells upon neural induction.

Mammalian embryonic stem (ES) cells can either self-renew or generate progenitor cells that have a more restricted developmental potential. This provides an important model system to ask how pluripotency, cell commitment and differentiation are regulated at the level of chromatin-based changes that distinguish stem cells from their differentiated progeny. Here we show that the differentiation of ES cells to neural progenitors results in dynamic changes in the epigenetic status of multiple genes that encode transcription factors critical for early embryonic development or lineage specification. In particular, we demonstrate that DNA replication at a subset of neural-associated genes including Pax3, Pax6, Irx3, Nkx2.9 and Mash1 is advanced upon neural induction, consistent with increased locus accessibility. Conversely, many ES-associated genes including Oct4, Nanog, Utf1, Foxd3, Cripto and Rex1 that replicate early in ES cells switch their replication timing to later in S-phase in response to differentiation. Detailed analysis of the Rex1 locus reveals that delayed replication extends to a 2.8 Mb region surrounding the gene and is associated with substantial reductions in the level of histone H3K9 and H4 acetylation at the promoter. These results show that loss of pluripotency (and lineage choice) is associated with extensive and predictable changes in the replication timing of key regulator genes.

Animals↗

Development of force adaptation during childhood.

Humans learn to make reaching movements in novel dynamic environments by acquiring an internal motor model of their limb dynamics. Here, the authors investigated how 4- to 11-year-old children (N = 39) and adults (N = 7) adapted to changes in arm dynamics, and they examined whether those data support the view that the human brain acquires inverse dynamics models (IDM) during development. While external damping forces were applied, the children learned to perform goal-directed forearm flexion movements. After changes in damping, all children showed kinematic aftereffects indicative of a neural controller that still attempted to compensate the no longer existing damping force. With increasing age, the number of trials toward complete adaptation decreased. When damping was present, forearm paths were most perturbed and most variable in the youngest children but were improved in the older children. The findings indicate that the neural representations of limb dynamics are less precise in children and less stable in time than those of adults. Such controller instability might be a primary cause of the high kinematic variability observed in many motor tasks during childhood. Finally, the young children were not able to update those models at the same rate as the older children, who, in turn, adapted more slowly than adults. In conclusion, the ability to adapt to unknown forces is a developmental achievement. The present results are consistent with the view that the acquisition and modification of internal models of the limb dynamics form the basis of that adaptive process.

Adaptation, Physiological↗

Abundant and dynamic expression of G protein-coupled P2Y receptors in mammalian development.

Extracellular ATP mediates diverse biological effects by activating two families of receptors, the P2X and P2Y receptors. There is growing evidence to show that activation of G protein-coupled P2Y receptors can produce trophic effects in many cell types. Yet the expression and function of the P2Y receptors in development has rarely been studied and has never been investigated in mammalian development. This study used the reverse transcription-polymerase chain reaction and immunohistochemistry to demonstrate the abundant and dynamic expression of P2Y receptors in rat development. These receptors were expressed in a wide range of embryonic structures, notably somites, skeletal muscle, the central and peripheral nervous system, the heart, lung, and liver. All the P2Y receptors studied were expressed as early as embryonic day 11, when most embryonic organs were far from being functional and still in the process of being formed. P2Y receptor proteins were strongly expressed in temporary, developmental structures that do not have a correlate in the adult animal, including the somites (P2Y1, P2Y2, and P2Y4) and the floor plate of the neural tube (P2Y1). P2Y receptors were also dynamically expressed, with receptor mRNA and protein being both up- and down-regulated at different developmental stages. The down-regulation of the P2Y1, 2, and 4 receptor proteins in skeletal muscle and heart, and the disappearance of the P2Y4 receptor from the brainstem and ventral white matter of the spinal cord postnatally, demonstrated that many P2Y receptors were likely to be involved in functions specific to embryonic life. Thus, these findings strongly suggest that P2Y receptors play an important role in the development of many tissues, and pioneer further studies into the role of purinergic signalling in development.

Adenosine Triphosphate↗

Linker histone variants control chromatin dynamics during early embryogenesis.

Complex transitions in chromatin structure produce changes in genome function during development in metazoa. Linker histones, the last component of nucleosomes to be assembled into chromatin, comprise considerably divergent subtypes as compared with core histones. In all metazoa studied, their composition changes dramatically during early embryogenesis concomitant with zygotic gene activation, leading to distinct functional changes that are still poorly understood. Here, we show that early embryonic linker histone B4, which is maternally expressed, is functionally different from somatic histone H1 in influencing chromatin structure and dynamics. We developed a chromatin assembly system with nucleosome assembly protein-1 as a linker histone chaperone. This assay system revealed that maternal histone B4 allows chromatin to be remodeled by ATP-dependent chromatin remodeling factor, whereas somatic histone H1 prevents this remodeling. Structural analysis shows that histone B4 does not significantly restrict the accessibility of linker DNA. These findings define the functional significance of developmental changes in linker histone variants. We propose a model that holds that maternally expressed linker histones are key molecules specifying nuclear dynamics with respect to embryonic totipotency.

Animals↗

The Spatiotemporal Genetic Architecture of Seed Vigor in Upland Cotton.

Seed vigor underpins uniform crop establishment, but its dynamic genetics are understudied. Combining high-resolution temporal phenotyping and genomics in upland cotton, we used the SeedRanger platform to record 17 image-based traits every 30 min over 120 h, revealing stage-specific heritability and identifying 541 seed-vigor loci. These loci show extensive pleiotropy and temporal coordination, forming a genetic network that preserves developmental continuity; 8.9% overlap regions under domestication selection, indicating concurrent optimization with fiber yield. Functional validation of FLA2, a candidate gene underlying a dynamic QTL, implicates auxin-mediated control of radicle elongation and cotyledon development. This temporal framework exposes dynamic genetic architecture and breeding targets for high-vigor crops.

Gossypium↗

Testing models of parental investment strategy and offspring size in ants.

Parental investment strategies can be fixed or flexible. A fixed strategy predicts making all offspring a single 'optimal' size. Dynamic models predict flexible strategies with more than one optimal size of offspring. Patterns in the distribution of offspring sizes may thus reveal the investment strategy. Static strategies should produce normal distributions. Dynamic strategies should often result in non-normal distributions. Furthermore, variance in morphological traits should be positively correlated with the length of developmental time the traits are exposed to environmental influences. Finally, the type of deviation from normality (i.e., skewed left or right, or platykurtic) should be correlated with the average offspring size. To test the latter prediction, we used simulations to detect significant departures from normality and categorize distribution types. Data from three species of ants strongly support the predicted patterns for dynamic parental investment. Offspring size distributions are often significantly non-normal. Traits fixed earlier in development, such as head width, are less variable than final body weight. The type of distribution observed correlates with mean female dry weight. The overall support for a dynamic parental investment model has implications for life history theory. Predicted conflicts over parental effort, sex investment ratios, and reproductive skew in cooperative breeders follow from assumptions of static parental investment strategies and omnipresent resource limitations. By contrast, with flexible investment strategies such conflicts can be either absent or maladaptive.

Animals↗

The development of time sense--from birth to object constancy.

This paper represents an attempt to delineate the developmental line of time sense from birth to object constancy, concentrating on those maturational and environmental factors which determine psychotemporal adaptation in infancy and early childhood. Observational data and clinical vignettes are used to support theoretical formulations. Time sense is understood as a subjective, dynamic emergence which evolves throughout the life cycle. Psychoanalysis has paid little attention to the theory of time, and much needs to be accomplished to formulate the developmental line of time for the remainder of the life cycle.

Adaptation, Psychological↗

Multifocal venous malformations: two interesting case presentations.

INTRODUCTION: Multiple venous abnormalities involving the orbit, head and neck regions have been previously described. We present two similar cases of low-flow orbital venous vascular malformations (VVMs) in association with multiple low-flow VVMs in the head and neck as well as in the peripheral limb. Literature search revealed that this association has not been previously reported. METHODS: Retrospective review of two patients with multifocal VVMs was performed. RESULTS: Case 1: A 46 year-old Chinese female had a history of multiple vascular lesions involving the right orbit, the tongue, right neck region, right arm and one finger. Valsalva manoeuvre resulted in distension of these lesions. CT scan of the orbits demonstrated bilateral low-flow VVMs. CT angiogram also revealed multiple developmental venous anomalies in the brain. Case 2: A 16 year-old Chinese female had a history of multiple venous malformations involving the neck, left forearm and oral region. Dynamic manoeuvres demonstrated the distensible nature of these lesions. MRI scans of the orbits showed bilateral extraconal low-flow VVMs. Similar mass lesions were seen on MRI scans of the neck. CONCLUSIONS: Multiple cervicofacial venous malformations with developmental abnormalities of the intracranial venous system have been described previously. However, their associations with similar VVMs in the peripheral limb regions have not been reported. Our cases illustrate this rare association. VVMs appear to be benign in nature with symptoms mainly due to mass effect. Management can be conservative in the absence of any sight threatening complication.

Adolescent↗

Fluorescence microscopy of calcium and synaptic vesicle dynamics during synapse formation in tissue culture.

The signal transduction process involved in the development of the nerve terminal is an intriguing question in developmental neurobiology. During the formation of the neuromuscular junction, presynaptic development is induced by growth cone's contact with the target muscle cell. Fluorescence microscopy with specific markers has made it possible to follow signalling events during this process. By using fluorescent calcium indicators, such as fura-2 and fluo-3, we found that a rise in intracellular calcium is elicited in the growth cone upon its contact with a target, and this calcium signal can also be elicited by local application of basic fibroblast growth factor. To monitor the clustering of synaptic vesicles in response to target contact, the fluorescent vesicular probe FMl-43 was used. With this probe, we observed that packets of synaptic vesicle are already present along the length of naïve neurite, which has not encountered its synaptic target. The activity-dependent loading of FMl-43 indicates that these packets can undergo exocytosis and endocytosis upon depolarization. Time-lapse recording showed that these packets are quite mobile. Upon target contact, synaptic vesicles become clustered and immobilized at the contact site. The methodology and instrumentation used in these studies are described in this article.

Animals↗

Nonlinear dynamics in pulsatile secretion of parathyroid hormone in normal human subjects.

In many biological systems, information is transferred by hormonal ligands, and it is assumed that these hormonal signals encode developmental and regulatory programs in mammalian organisms. In contrast to the dogma of endocrine homeostasis, it could be shown that the biological information in hormonal networks is not only present as a constant hormone concentration in the circulation pool. Recently, it has become apparent that hormone pulses contribute to this hormonal pool, which modulates the responsiveness of receptors within the cell membrane by regulation of the receptor synthesis, movement within the membrane layer, coupling to signal transduction proteins and internalization. Phase space analysis of dynamic parathyroid hormone (PTH) secretion allowed the definition of a (in comparison to normal subjects) relatively quiet "low dynamic" secretory pattern in osteoporosis, and a "high dynamic" state in hyperparathyroidism. We now investigate whether this pulsatile secretion of PTH in healthy men exhibits characteristics of nonlinear determinism. Our findings suggest that this is conceivable, although on the basis of presently available data and techniques, no proof can be established. Nevertheless, pulsatile secretion of PTH might be a first example of nonlinear deterministic dynamics in an apparently irregular hormonal rhythm in human physiology. (c) 1995 American Institute of Physics.

Journal Article↗

Modeling the dynamic interplay between general and specific change in children's conceptual understanding.

In introducing this chapter, I pointed out that traditional theories of learning and of cognitive development were in conflict with regard to the effects of specific learning. Developmental theorists saw general structures as influencing specific learning but not being affected by it, whereas learning theorists took the opposite view - that general structures (if they existed) were affected only by specific experiences. In the formulation of neo-Piagetian theory, both general and specific effects were acknowledged; however, general effects were assigned to mental capacity and specific ones to the child's schematic repertoire. Thus, the possibility of reciprocal influence did not emerge (or at least was not explored). In the present chapter, I have proposed the existence of such a reciprocal influence and explored its consequences. At a general level, the two consequences that follow are (1) that the overall pace of development is accelerated and (2) that the profile of development is evened out because benefits obtained from high-frequency learning experiences are passed on, via the mediation of the central conceptual structure, to low-frequency ones. These two effects were then advanced as one possible explanation for the difference in the data obtained between different cultures and different social classes. In the former case, the explanation utilized the notion that the benefits of high-frequency learning could be passed on to low-frequency situations via the mediation of general structures; in the latter case, the explanation drew on the notion that experiential loops can accelerate or decelerate development by magnifying experiential differences that are relatively small but that prevail across most of the tasks that a child encounters. The last half of the present chapter was devoted to specifying the dynamics of this sort of interaction in mathematical terms. The data that were obtained in Chapters III and V were extremely regular and showed an even pattern of development across different tasks; hence, they could conceivably be modeled with single curves or even straight lines. The mathematical model chosen to fit these findings was much more complex, however. Each growth curve was generated by an expression that contained a dynamic tension between two opposing categories of effect: those whose tendency is to make different developmental pathways disperse (different growth rates and the effect of compounding) and those whose tendency is to hold development to a single course (the constraints imposed by a growing carrying capacity and the "binding together" or "squeezing" effect generated by the reciprocal feedback loop). The disadvantage of this sort of modeling is clearly its complexity. An equally clear advantage, however, is that it allows one to provide a unified explanation for a set of data that might otherwise seem quite disparate and to express relations in quantitative rather than merely qualitative terms. This, in turn, permits one to check the entire set of proposed relations for their consistency, and to explore the dynamic pattern of their interaction, by conducting "intellectual experiments" and checking them against common sense and/or existing data sets. In the present chapter, this approach has been used for the effects of social class and of culture. In principle, however, it could potentially be used equally to explore the effects of other variables, such as those that underlie intellectual retardation and/or "giftedness". At least for the moment, then, the mathematical modeling approach looks promising.

Child↗

Roles for alpha 1 connexin in morphogenesis of chick embryos revealed using a novel antisense approach.

Gap junctional communication has been implicated in embryonic development and pattern formation. The gap junction protein, alpha 1 connexin (Cx43) is expressed in dynamic and spatially restricted patterns in the developing chick embryo and its expression correlates with many specific developmental events. High levels of expression are found in regions of budding, which leads to shaping and appears to be a necessary prelude for tissue fusions. In order to investigate the role of alpha 1 connexin in these morphogenetic events, we developed a novel method of applying unmodified antisense deoxyoligonucleotides (ODNs) to chick embryos. The use of pluronic gel to deliver antisense ODNs has allowed us to regulate the expression of alpha 1 connexin protein, both spatially and temporally. This "knockdown" results in some striking developmental defects that mimic some common congenital abnormalities, such as spina bifida, anencephaly, myeloschisis, limb malformation, cleft palate, failure of hematopoiesis, and cardiovascular deformity. The results imply a major role for alpha 1 connexin communication in the integration of signaling required for pattern formation during embryonic development. This novel antisense technique may also be widely applicable.

Animals↗

Plant chromatin: development and gene control.

It is increasingly clear that chromatin is not just a device for packing DNA within the nucleus but also a dynamic material that changes as cellular environments alter. The precise control of chromatin modification in response to developmental and environmental cues determines the correct spatial and temporal expression of genes. Here, we review exciting discoveries that reveal chromatin participation in many facets of plant development. These include: chromatin modification from embryonic and meristematic development to flowering and seed formation, the involvement of DNA methylation and chromatin in controlling invasive DNA and in maintenance of epigenetic states, and the function of chromatin modifying and remodeling complexes such as SWI/SNF and histone acetylases and deacetylases in gene control. Given the role chromatin structure plays in every facet of plant development, chromatin research will undoubtedly be integral in both basic and applied plant biology.

Animals↗

Compartmentalized morphogenesis in epithelia: from cell to tissue shape.

During development, embryonic tissues are shaped in a species-specific manner. Yet, across species, general classes of tissue remodeling events occur, such as tissue infolding and tissue elongation. The spatiotemporal control of these morphogenetic processes is responsible for the organization of different body plans, as well as for organogenesis. Cell morphogenesis in a mesenchyme contributes to the shaping of embryonic tissues. Epithelial cells, despite that they need to maintain an apicobasal organization, play an equally important role during morphogenesis. Moving from apical to basal, we review compartmentalized cellular rearrangements underlying tissue remodeling in Drosophila and compare them with those found in other organisms. Contractile activity at the apical surface triggers tissue folding and invagination. The regulation of adhesion at adherens junctions controls polarized neighbor exchange during intercalation and tissue elongation. Basolateral protrusive activity underlies other cases of intercalation. These localized cell shape changes are spatially regulated by developmental signals. Some signals define a local change in cell behavior (e.g., apical constriction), others orient a dynamic process in the plane of the tissue (e.g., junction remodeling).

Actins↗