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Language disorder in schizophrenia as a developmental learning disorder.

Receptive language disorder in schizophrenia is hypothesized to represent a learning disorder that involves a neurodevelopmental etiology. It is argued that a preexisting developmental language disorder may characterize a subset of schizophrenia patients. A primary deficit in the temporal dynamics of brain function is assumed to cause receptive language disorder in schizophrenia. This hypothesized core deficit includes both disturbance in the processing of rapid, sequential information and disruptions to patterns of brain activation and synchronization. These timing deficits may alter the way associative connections are formed and/or accessed in semantic memory. It is suggested that abnormalities in second-messenger pathways of subcortical-cortical circuitry offer an etiological nexus for language dysfunction in schizophrenia and developmental dyslexia.

Brain↗

Segmentation and somitogenesis derived from phase dynamics in growing oscillatory media.

The formation of spatially repetitive structures along the growth axis of a developing embryo is a common theme in developmental biology. Here we apply the novel flow-distributed oscillator (FDO) mechanism of wave pattern formation to the problem of axial segmentation in general and to somitogenesis in particular. We argue that the conditions for formation of FDO waves are satisfied during somitogenesis in the chick and mouse and that the waves of gene expression observed in these species arise from phase dynamics in a growing oscillatory medium. We substantiate this claim by showing that the FDO mechanism allows the waves to be mimicked by an inorganic experiment and that it predicts a wavelength that coincides with that observed experimentally. To see whether the FDO mechanism is compatible with other aspects of somitogenesis, we construct an FDO-based model of somitogenesis and successfully test it against a number of experimental observations, including the effect of heat shock. Our analysis provides a rigorous physical basis for the hypothesis that the phase dynamics of a segmental clock controls important stages of segmentation during somitogenesis in the chick and mouse as well as in other organisms that undergo segmentation during their axial growth.

Animals↗

An efficient in situ hybridization protocol for multiple tissue sections and probes on miniaturized slides.

To facilitate detection of gene activity in tissue sections we combined common protocols of in situ hybridization on tissue sections (TSISH) with the technique of whole-mount in situ hybridization (WMISH). Miniature glass slides for mounting tissue sections were cut from regular microscope slides and handled for in situ hybridization in laboratory-made 2-ml containers (baskets) similar to those originally used for WMISH on Drosophila embryos. A salient point of the method is the use of airtight reaction vessels placed in a dry thermostat for critical hybridization steps as this facilitates reproducible and stringent hybridization conditions which are difficult to achieve on tissue sections otherwise. The practicability of the method is illustrated on consecutive serial frozen sections of murine neonatal cerebellum hybridized for math1 and neuroD, two developmentally regulated genes with distinct expression patterns. For both genes excellent spatial resolution and a highly dynamic range of signal intensity was obtained. The approach enables simple processing of multiple probes, allows the efficient and economic use of small tissue samples and is amenable to automation.

Animals↗

Cloning and developmental expression of a zebrafish meis2 homeobox gene.

We show here that a zebrafish meis2 gene homolog has a dynamic expression pattern in the developing mesoderm and central nervous system. Meis family homeodomain proteins are known to act as cofactors with other homeodomain proteins. We find expression of meis2.1 in the developing zebrafish hindbrain and somites, correlating with reported sites of zebrafish hox gene expression, as well as in presumptive cerebellum, midbrain, retina and ventral forebrain. The expression pattern shares some, but not all, features with that of murine Meis2.

Amino Acid Sequence↗

Aggression from a developmental perspective: genes, environments and interactions.

Genetic influences on the social behaviours of non-human mammals are ubiquitous, powerful and readily detected. But demonstrations that social behaviours are influenced by genes constitute only part of the story. Developmental findings have helped complete the picture. Specifically, these studies show that: (1) genetic effects for aggressive behaviours are highly malleable over the course of development; (2) genetic influences on aggressive behaviour are more dynamic, easily achieved and open to rapid manipulation than has been recognized in current models of social evolution and behavioural genetics; (3) developmental timing has a significant impact upon the nature of the genetic effects observed in aggressive behaviours. These empirical results are consistent with the view that social behaviours are among the first features to be influenced by genetic selection and by environmental experience. Social actions have distinctive properties in adaptation because they organize the space between the organism and the environment and promote rapid, selective and novel accommodations. The modern integrative view of the development of individual-in-context brings attention to the correlation between constraints within and external to individuals. This paper reviews findings on how these processes become integrated over time in individuals and species, and their implications for the nurture of nature.

Aggression↗

Structures in focus--filopodia.

Filopodia are thin cell surface extensions filled with tight parallel bundles of actin filaments. They are highly dynamic structures which rapidly extend and retract as well as sweep up and down and from side to side, and can be found at the leading edge of many types of motile cells such as fibroblasts and keratinocytes, as well as the growth cone tips of migrating axons. Cells appear to use filopodia to explore the extracellular matrix (ECM) and surfaces of other cells, identifying appropriate targets for adhesion or in the case of a migrating growth cone, for sensing guidance cues that enable the axon to navigate to it's appropriate target. As well as this sensory role, filopodia have also recently been shown to play an important mechanical role in epithelial adhesion, and are likely to be key players in developmental processes that require migrating epithelial sheets to zipper and fuse to one another. Their dynamic properties as well as their tendency to be damaged or lost after fixation mean they are best analysed using live imaging techniques. As this field improves, the number of tissues in which filopodia are seen to be playing key roles is fast increasing.

Animals↗

Cellular consequences in the brain and liver of age-specific selection for rate of development in mice.

Changes in cell number (hyperplasia) and cell size (hypertrophy) in the brain and liver are described for mice subjected to 24 generations of age-specific restricted index selection for rate of development in body weight. One selection treatment (E) altered rate of development between birth and 10 days of age, another treatment (L) involved changes in rate of development between 28 and 56 days of age, while a third control treatment (C) involved random selection. Each selection treatment was replicated three times. These age-specific selection treatments focused on intervals during ontogeny when different developmental processes (hypertrophy or hyperplasia) were more predominant in the control of growth. Significant changes in brain and liver weight occurred at both 28 and 70 days of age. Early selection (E) generated significant changes in the number of cells in the brain while later selection (L) had no effect since the brain had stopped growth before selection was initiated. For the liver, early and late selection produced significant effects on both cell number and cell size. These results describe the dynamic and multidimensional aspects of selection in terms of its ability to alter different cellular and developmental components of complex morphological traits.

Aging↗

Model for cooperative control of positional information in Drosophila by bicoid and maternal hunchback.

The blastoderm of the fruit fly Drosophila melanogaster is unusually well suited for analysis of fundamental questions in animal development. One such question is how genes specify the positional information which determines the developmental pathways (fate) of cells at appropriate spatial locations. In this paper we propose a dynamical model of gene regulation which explicitly describes how positional information is used in the blastoderm. The model is applied to analyze important experimental findings on the dependence of cell fate on the concentration of the Bicoid morphogen. The model shows that positional information in the presumptive middle body is cooperatively determined by maternal products of the bicoid and hunchback genes.

Animals↗

Expression of tissue transglutaminase in the developing chicken limb is associated both with apoptosis and endochondral ossification.

The cross-linking enzyme tissue transglutaminase (tTG) participates in a variety of cellular functions. To assess its contribution to extracellular and intracellular processes during development we cloned the cDNA for chicken heart tissue transglutaminase and localized the sites of transglutaminase expression by in situ hybridization and immunohistochemistry. Compared with the chicken red blood cell transglutaminase cDNA, the heart cDNA encodes a transglutaminase with an amino-terminal truncation. The truncated enzyme retains full catalytic activity and is GTP-inhibitable. Tissue transglutaminase expression was observed in developmentally transient structures in embryonic chicken limb at day 7.5 of incubation suggesting that its expression is dynamically regulated during limb morphogenesis. The major morphogenetic events of the limb associated with transglutaminase expression were cartilage maturation during skeletal development, interdigital apoptosis, and differentiation of skeletal muscle. Maturation of the cartilage during endochondral ossification was characterized by intra- and extracellular transglutaminase accumulation in the zone of hypertrophic chondrocytes. Only intracellular enzyme could be detected in mesenchymal cells of the prospective joints, in apoptotic cells of the interdigital web, and in skeletal muscle myoblasts. An apparently constitutive expression of tissue transglutaminase was found in vascular endothelial cells corresponding to the adult expression pattern. The dynamic pattern of transglutaminase expression during morphogenesis suggests that tissue remodeling is a major trigger for transglutaminase induction.

Animals↗

Development and localisation of GABA(A) receptor alpha1, alpha2, beta2 and gamma2 subunit mRNA in the chick optic tectum.

An in situ hybridisation technique was used to analyse the spatial and temporal pattern of expression of the mRNA encoding the four gamma-aminobutyric acid A (GABA(A)) receptor subunits (alpha1, alpha2, beta2, and gamma2) in the developing chick optic tectum. As a rule, layer i, layer h, and transient cell compartment 3 (TCC3) show the highest levels of expression, especially of alpha1, alpha2 and beta2, which undergo striking changes as a function of time. Apart from these common features, the global pattern is highly complex and dynamic. Such complexity derives from the fact that each subunit exhibits a characteristically distinct pattern of expression and the temporal evolution of each differs in the different layers of the tectum. The influence of several developmental cell behaviours such as proliferation, neuronal migration, programmed cell death, and differentiation must be taken into account to understand pattern complexity and dynamics. Our results suggest that differences in the rate of subunit expression, particularly of alpha1, alpha2, and beta2, could have significant consequences on GABA(A) receptor complex subunit composition along development and on the functional properties of the GABA neurotransmitter system.

Animals↗

Developmental shifts in the ability of infants with Down syndrome to produce treadmill steps.

BACKGROUND AND PURPOSE: In this study, we used a dynamic systems strategy to examine longitudinally the ability of infants with Down syndrome to produce alternating steps when supported on a motorized treadmill. SUBJECTS: Seven infants participated, ranging in age from 8 to 11 months at entry into the study and 13 to 29 months at their final session. METHODS: Data were collected in the infants' homes on a monthly basis. Testing continued until each subject produced consistent alternating step patterns during three consecutive test sessions. RESULTS: All infants responded by producing alternating steps, on average, 13.3 months before they walked independently, but they initiated this response at a wide range of chronological ages and significantly later than reported previously for nondisabled infants. Similar developmental variables (control parameters) marked the shift into responsiveness to the treadmill context for all infants with Down syndrome, but these variables differed from those identified for nondisabled infants. CONCLUSION AND DISCUSSION: With age, alternating treadmill stepping became a more stable response, although the relative timing of interlimb coordination (phase lag) of the step cycles remained quite variable across ages. We discuss our results relative to the usefulness of dynamic systems theory in understanding delayed development and the possibilities of pursuing the treadmill paradigm as an intervention approach.

Down Syndrome↗

Development, microevolution, and social behavior.

The central questions of social development--from the roots of mother-infant attachment to the plasticity of aggressive behavior--pivot on the relations between genetic and ontogenetic sources of variance. It is proposed that (a) developmental, experiential, and microevolutionary processes typically collaborate, rather than compete, in achieving social adaptation; (b) social behavior patterns are mostly closed to modification in the course of development and across generations, but avenues of vulnerability exist in ontogeny and microevolution for dynamic, rapid, and reversible changes in key features; (c) a general avenue for change is delay or acceleration in the developmental onset of one or more features of the behavior pattern, which in turn modifies the functions and properties of the adaptive configuration; and (d) the features of social behavior that are open to rapid change in ontogeny should be open as well to rapid changes in microevolution, although different underlying processes may be involved. Empirical findings from the investigation of aggressive interactions are used to illustrate this proposal on the dual genesis and coincident adaptation of social behaviors.

Animals↗

Developmental and Tissue-Specific Structural Alterations of the Cell-Wall Polysaccharides of Arabidopsis thaliana Roots.

The plant cell wall is a dynamic structure that plays important roles in growth and development and in the interactions of plants with their environment and other organisms. We have used monoclonal antibodies that recognize different carbohydrate epitopes present in plant cell-wall polysaccharides to locate these epitopes in roots of developing Arabidopsis thaliana seedlings. An epitope in the pectic polysaccharide rhamnogalacturonan I is observed in the walls of epidermal and cortical cells in mature parts of the root. This epitope is inserted into the walls in a developmentally regulated manner. Initially, the epitope is observed in atrichoblasts and later appears in trichoblasts and simultaneously in cortical cells. A terminal [alpha]-fucosyl-containing epitope is present in almost all of the cell walls in the root. An arabinosylated (1->6)-[beta]-galactan epitope is also found in all of the cell walls of the root with the exception of lateral root-cap cell walls. It is striking that these three polysaccharide epitopes are not uniformly distributed (or accessible) within the walls of a given cell, nor are these epitopes distributed equally across the two walls laid down by adjacent cells. Our results further suggest that the biosynthesis and differentiation of primary cell walls in plants are precisely regulated in a temporal, spatial, and developmental manner.

Journal Article↗

Motor development. A new synthesis.

The study of the acquisition of motor skills, long moribund in developmental psychology, has seen a renaissance in the last decade. Inspired by contemporary work in movement science, perceptual psychology, neuroscience, and dynamic systems theory, multidisciplinary approaches are affording new insights into the processes by which infants and children learn to control their bodies. In particular, the new synthesis emphasizes the multicausal, fluid, contextual, and self-organizing nature of developmental change, the unity of perception, action, and cognition, and the role of exploration and selection in the emergence of new behavior. Studies are concerned less with how children perform and more with how the components cooperate to produce stability or engender change. Such process approaches make moot the traditional nature-nurture debates.

Aptitude↗

Unilateral neglect: a theory of proprioceptive space of a stimulus as determined by the cerebellar component of motor efference copy (and is autism a special case of neglect).

Unilateral neglect is a devastating condition, which manifests as a loss of a person's spatial awareness opposite the damaged side of the brain. It challenges our conception of the seat of the soul and its explanation is at the heart of the mind-body problem. A heuristic definition of the dorsal stream of a modality is here based on the categorization of parietal networks by the cerebellar component of motor efference copy. Taking this premise, the proprioceptive space of a stimulus is established as a concept in this paper. It is proposed that unilateral neglect is typically a dysfunction of proprioceptive space of a stimulus associated with lesions of the dorsal stream. Furthermore, most experimental findings of unilateral visual neglect (and by extrapolation, other sensory modalities), can be explained by two developmental mechanisms by which the proprioceptive space of a stimulus is encoded in the parietal cortex. Its right and left hemisphere representation can be dissociated from the hemifield of presentation of perceptual information, such that the left hemifield can have a left hemisphere representation through callosal connections and likewise, the right hemifield can have a right hemifield representation. The processing of a sensory stimulus in either parietal hemisphere is dynamically determined as shown by experimental modulation of performance. A theory of historical precedence will provide a developmental background to the organization of proprioceptive space and will invoke separate models according to specified terms of engagement. A model based on the expansion and contraction of the proprioceptive space of a stimulus as a gradient across both hemispheres and modulated by concurrent proprioceptive state will be differentiated from a model that is non-graduating but competitive and lacks such modulation. In other words, the dorsal representation of a sensory stimulus in the former case is shared to a varying degree by the two parietal hemispheres, whereas in the latter case the representation of left and right aspects of the same object stimulus is strictly divided between the two hemispheres. A further hypothesis of a dorsoventral gradient of the peripheral and foveal components of proprioceptive space characterizing dorsal stream networks will predict the double dissociation revealed by experimental paradigms. It will explain why some patients show neglect only in foveal while others only in peripheral vision. The paper proposes to unify neglect, extinction and optic ataxia on the one hand, and spatial and object-based neglect on the other hand, under a singularly proficient paradigmatic structure. A binding model as described is a component theory that acknowledges how the involved pathways or transitional zones in a pathway may contribute to a differential clinical picture as one progresses from posterior to anterior parietal cortex. Finally, a brief discussion is given on how autistic subjects neglect spatial cues and the inability of a spatial cognitive transformation underlies the impairments postulated for 'a theory of mind'.

Autistic Disorder↗

A biphasic pattern of gene expression during mouse retina development.

BACKGROUND: Between embryonic day 12 and postnatal day 21, six major neuronal and one glia cell type are generated from multipotential progenitors in a characteristic sequence during mouse retina development. We investigated expression patterns of retina transcripts during the major embryonic and postnatal developmental stages to provide a systematic view of normal mouse retina development, RESULTS: A tissue-specific cDNA microarray was generated using a set of sequence non-redundant EST clones collected from mouse retina. Eleven stages of mouse retina, from embryonic day 12.5 (El2.5) to postnatal day 21 (PN21), were collected for RNA isolation. Non-amplified RNAs were labeled for microarray experiments and three sets of data were analyzed for significance, hierarchical relationships, and functional clustering. Six individual gene expression clusters were identified based on expression patterns of transcripts through retina development. Two developmental phases were clearly divided with postnatal day 5 (PN5) as a separate cluster. Among 4,180 transcripts that changed significantly during development, approximately 2/3 of the genes were expressed at high levels up until PN5 and then declined whereas the other 1/3 of the genes increased expression from PN5 and remained at the higher levels until at least PN21. Less than 1% of the genes observed showed a peak of expression between the two phases. Among the later increased population, only about 40% genes are correlated with rod photoreceptors, indicating that multiple cell types contributed to gene expression in this phase. Within the same functional classes, however, different gene populations were expressed in distinct developmental phases. A correlation coefficient analysis of gene expression during retina development between previous SAGE studies and this study was also carried out. CONCLUSION: This study provides a complementary genome-wide view of common gene dynamics and a broad molecular classification of mouse retina development. Different genes in the same functional clusters are expressed in the different developmental stages, suggesting that cells might change gene expression profiles from differentiation to maturation stages. We propose that large-scale changes in gene regulation during development are necessary for the final maturation and function of the retina.

Animals↗

Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia.

Neurodevelopmental models for the pathology of schizophrenia propose both polygenetic and environmental risks, as well as early (pre/perinatal) and late (usually adolescent) developmental brain abnormalities. With the use of brain mapping algorithms, we detected striking anatomical profiles of accelerated gray matter loss in very early-onset schizophrenia; surprisingly, deficits moved in a dynamic pattern, enveloping increasing amounts of cortex throughout adolescence. Early-onset patients were rescanned prospectively with MRI, at 2-year intervals at three time points, to uncover the dynamics and timing of disease progression during adolescence. The earliest deficits were found in parietal brain regions, supporting visuospatial and associative thinking, where adult deficits are known to be mediated by environmental (nongenetic) factors. Over 5 years, these deficits progressed anteriorly into temporal lobes, engulfing sensorimotor and dorsolateral prefrontal cortices, and frontal eye fields. These emerging patterns correlated with psychotic symptom severity and mirrored the neuromotor, auditory, visual search, and frontal executive impairments in the disease. In temporal regions, gray matter loss was completely absent early in the disease but became pervasive later. Only the latest changes included dorsolateral prefrontal cortex and superior temporal gyri, deficit regions found consistently in adult studies. These emerging dynamic patterns were (i) controlled for medication and IQ effects, (ii) replicated in independent groups of males and females, and (iii) charted in individuals and groups. The resulting mapping strategy reveals a shifting pattern of tissue loss in schizophrenia. Aspects of the anatomy and dynamics of disease are uncovered, in a changing profile that implicates genetic and nongenetic patterns of deficits.

Adolescent↗

Dynamics of peroxisome assembly and function.

Recent studies in human cells and in the yeast Yarrowia lipolytica have shown that peroxisomes consist of numerous structurally distinct subcompartments that differ in their import competency for various proteins and are related through a time-ordered conversion of one subcompartment to another. Our studies have implicated the fusion of small peroxisomal precursors as an early event in the multistep assembly of peroxisomes operating in Y. lipolytica. Newly discovered unexpected roles for peroxisomes in specific developmental programs have expanded the remarkable plasticity of peroxisomal functions. Here, we highlight recent discoveries on the highly dynamic nature of peroxisome assembly and function and suggest questions for future research in these areas.

Animals↗