CONGENITAL ANOMALIES, Issue 2 2006
Rengasamy Padmanabhan
ABSTRACT Spina bifida, anencephaly, and encephalocele are commonly grouped together and termed neural tube defects (NTD). Failure of closure of the neural tube during development results in anencephaly or spina bifida aperta but encephaloceles are possibly post-closure defects. NTD are associated with a number of other central nervous system (CNS) and non-neural malformations. Racial, geographic and seasonal variations seem to affect their incidence. Etiology of NTD is unknown. Most of the non-syndromic NTD are of multifactorial origin. Recent in vitro and in vivo studies have highlighted the molecular mechanisms of neurulation in vertebrates but the morphologic development of human neural tube is poorly understood. A multisite closure theory, extrapolated directly from mouse experiments highlighted the clinical relevance of closure mechanisms to human NTD. Animal models, such as circle tail, curly tail, loop tail, shrm and numerous knockouts provide some insight into the mechanisms of NTD. Also available in the literature are a plethora of chemically induced preclosure and a few post-closure models of NTD, which highlight the fact that CNS malformations are of hetergeneitic nature. No Mendelian pattern of inheritance has been reported. Association with single gene defects, enhanced recurrence risk among siblings, and a higher frequency in twins than in singletons indicate the presence of a strong genetic contribution to the etiology of NTD. Non-availability of families with a significant number of NTD cases makes research into genetic causation of NTD difficult. Case reports and epidemiologic studies have implicated a number of chemicals, widely differing therapeutic drugs, environmental contaminants, pollutants, infectious agents, and solvents. Maternal hyperthermia, use of valproate by epileptic women during pregnancy, deficiency and excess of certain nutrients and chronic maternal diseases (e.g. diabetes mellitus) are reported to cause a manifold increase in the incidence of NTD. A host of suspected teratogens are also available in the literature. The UK and Hungarian studies showed that periconceptional supplementation of women with folate (FA) reduces significantly both the first occurrence and recurrence of NTD in the offspring. This led to mandatory periconceptional FA supplementation in a number of countries. Encouraged by the results of clinical studies, numerous laboratory investigations focused on the genes involved in the FA, vitamin B12 and homocysteine metabolism during neural tube development. As of today no clinical or experimental study has provided unequivocal evidence for a definitive role for any of these genes in the causation of NTD suggesting that a multitude of genes, growth factors and receptors interact in controlling neural tube development by yet unknown mechanisms. Future studies must address issues of gene-gene, gene-nutrient and gene,environment interactions in the pathogenesis of NTD. [source]

Assembling microtubules disintegrate the postsynaptic density in vitro

CYTOSKELETON, Issue 1 2007
Li-Ping Lo
Abstract The postsynaptic density (PSD), a disk-shaped protein aggregation of several hundred nm in diameter, plays important roles in the signal transduction and molecular organization of the excitatory synapses in mammalian CNS. The PSD resides in the microfilament-enriched cytoplasm of dendritic spines where the transient appearance of microtubules has been reported. When PSD isolated from porcine brain was incubated with polymerizing ,,,-tubulins, its turbidity became greater than that of the original PSD, suggesting that the PSD's structure was altered upon incubating with assembling microtubules. By transmission electron microscopy, smaller PSD fragments and several novel structures, including holes and finger-like extensions, were found in the PSD after incubation with assembling microtubules, but not in the original PSD or in the PSD incubated with ,,,-tubulins pretreated with vincristine. The results suggest that the interactions with assembling microtubules may result in the formation of holes in the PSD, and the rupture of these holes subsequently leads to the formation of smaller PSD fragments. Cell Motil. Cytoskeleton 2006. © 2006 Wiley-Liss, Inc. [source]

Epigenetic regulation in neural stem cell differentiation

DEVELOPMENT GROWTH & DIFFERENTIATION, Issue 6 2010
Berry Juliandi
The central nervous system (CNS) is composed of three major cell types , neurons, astrocytes, and oligodendrocytes , which differentiate from common multipotent neural stem cells (NSCs). This differentiation process is regulated spatiotemporally during the course of mammalian development. It is becoming apparent that epigenetic regulation is an important cell-intrinsic program, which can interact with transcription factors and environmental cues to modulate the differentiation of NSCs. This knowledge is important given the potential of NSCs to produce specific CNS cell types that will be beneficial for clinical applications. Here we review recent findings that address molecular mechanisms of epigenetic and transcription factor-mediated regulation that specify NSC fate during CNS development, with a particular focus on the developing mammalian forebrain. [source]

Development of three-dimensional architecture of the neuroepithelium: Role of pseudostratification and cellular ,community'

DEVELOPMENT GROWTH & DIFFERENTIATION, Issue 2008
Takaki Miyata
This review discusses the development of the neuroepithelium (NE) and its derivative ventricular zone (VZ), from which the central nervous system (CNS) is formed. First, the histological features of the NE and VZ are summarized, highlighting the phenomenon of pseudostratification, which is achieved by polarization and interkinetic nuclear migration (INM) of neural progenitor cells. Next, our current understanding of the cellular and molecular mechanisms and biological significance of INM and pseudostratification are outlined. The recent three-dimensional time-lapse observations revealing heterogeneity in cell lineages within the NE and VZ are also described, focusing on the neuronal lineage. Finally, the necessity of comprehensive studies on cell-cell interactions in the NE/VZ is discussed, as well as the importance of electrophysiological and biomechanical approaches. In particular, we suggest that a systems biology approach to the NE/VZ as a cellular ,community' may be fruitful. [source]

Activity-based restorative therapies: Concepts and applications in spinal cord injury-related neurorehabilitation

DEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2009
Cristina L. Sadowsky
Abstract Physical rehabilitation following spinal cord injury-related paralysis has traditionally focused on teaching compensatory techniques, thus enabling the individual to achieve day-to-day function despite significant neurological deficits. But the concept of an irreparable central nervous system (CNS) is slowly being replaced with evidence related to CNS plasticity, repair, and regeneration, all related to persistently maintaining appropriate levels of neurological activity both below and above the area where the damage occurred. It is now possible to envision functional repair of the nervous system by implementing rehabilitative interventions. Making the transition from "bench to bedside" requires careful analysis of existing basic science evidence, strategic focus of clinical research, and pragmatic implementation of new therapeutic tools. Activity, defined as both function specific motor task and exercise appears to be a necessity for optimization of functional, metabolic, and neurological status in chronic paralysis. Crafting a comprehensive rehabilitative intervention focused on functional improvement through neurological gains seems logical. The terms activity-based restorative therapies, activity-based therapies, and activity-based rehabilitation have been coined in the last 10 years to describe a new fundamental approach to deficits induced by neurological paralysis. The goal of this approach is to achieve activation of the neurological levels located both above and below the injury level using rehabilitation therapies. This article reviews basic and clinical science evidence pertaining to implementation of physical activity and exercise as a therapeutic tool in the management of chronic spinal cord-related neurological paralysis. © 2009 Wiley-Liss, Inc. Dev Disabil Res Rev 2009;15:112,116. [source]

The nervous system and gastrointestinal function

DEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2008
Muhammad A. Altaf
Abstract The enteric nervous system is an integrative brain with collection of neurons in the gastrointestinal tract which is capable of functioning independently of the central nervous system (CNS). The enteric nervous system modulates motility, secretions, microcirculation, immune and inflammatory responses of the gastrointestinal tract. Dysphagia, feeding intolerance, gastroesophageal reflux, abdominal pain, and constipation are few of the medical problems frequently encountered in children with developmental disabilities. Alteration in bowel motility have been described in most of these disorders and can results from a primary defect in the enteric neurons or central modulation. The development and physiology of the enteric nervous system is discussed along with the basic mechanisms involved in controlling various functions of the gastrointestinal tract. The intestinal motility, neurogastric reflexes, and brain perception of visceral hyperalgesia are also discussed. This will help better understand the pathophysiology of these disorders in children with developmental disabilities. © 2008 Wiley-Liss, Inc. Dev Disabil Res Rev 2008;14:87,95. [source]

Neurophysiology of hunger and satiety

DEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2008
Pauline M. Smith
Abstract Hunger is defined as a strong desire or need for food while satiety is the condition of being full or gratified. The maintenance of energy homeostasis requires a balance between energy intake and energy expenditure. The regulation of food intake is a complex behavior. It requires discrete nuclei within the central nervous system (CNS) to detect signals from the periphery regarding metabolic status, process and integrate this information in a coordinated manner and to provide appropriate responses to ensure that the individual does not enter a state of positive or negative energy balance. This review of hunger and satiety will examine the CNS circuitries involved in the control of energy homeostasis as well as signals from the periphery, both hormonal and neural, that convey pertinent information regarding short-term and long-term energy status of the individual. © 2008 Wiley-Liss, Inc. Dev Disabil Res Rev 2008;14:96,104. [source]

Neurocognitive effects of treatment for childhood cancer

DEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 3 2006
Robert W. Butler
Abstract We review research on the neuropsychological effects that central nervous system (CNS) cancer treatments have on the cognitive abilities of children and adolescents. The authors focus on the two most common malignancies of childhood: leukemias and brain tumors. The literature review is structured so as to separate out earlier studies, generally those published prior to 1995, as opposed to manuscripts that have been published within the past decade. This is an important distinction for both leukemia and brain tumors. Earlier studies were ground breaking in that they began to map out what could be expected in terms of intelligence and academic problems in survivors of pediatric malignancies. Survivorship in this population has and continues to markedly increase and this is largely due to changes in treatment protocols. Research on neurocognitive effects of disease and treatment in pediatric oncology has become increasingly sophisticated, and this literature review not only reflects this trend, but highlights the growing collaboration between neuropsychology, cognitive neuroscience, and neuro-imaging. Thus, our goal was to provide a historical foundation, lead the reader towards the progression of research methodology up to the current state of the art, and perhaps most importantly, discuss future directions. These directions are especially relevant to the concepts of remediation and treatment of cognitive problems, and this is emphasized at the conclusion of the review. MRDD Research Reviews 2006;12:184,191. © 2006 Wiley-Liss, Inc. [source]

Applications of gene targeting technology to mental retardation and developmental disability research

DEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 4 2005
Aurea F. Pimenta
Abstract The human and mouse genome projects elucidated the sequence and position map of innumerous genes expressed in the central nervous system (CNS), advancing our ability to manipulate these sequences and create models to investigate regulation of gene expression and function. In this article, we reviewed gene targeting methodologies with emphasis on applications to CNS development and neurodevelopmental disorders. © 2005 Wiley-Liss, Inc. MRDD Research Reviews 2005;11:295,302. [source]

Assessment of gestational age and neuromaturation

DEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 1 2005
Marilee C. Allen
Abstract Neuromaturation is the functional development of the central nervous system (CNS). It is by its very nature a dynamic process, a continuous interaction between the genome and first the intrauterine environment, then the extrauterine environment. Understanding neuromaturation and being able to measure it is fundamental to infant neurodevelopmental assessment. Fetal and preterm neuromaturation has become easier to observe with the advent of prenatal ultrasonography and neonatal intensive care units. A number of measures of degree of fetal maturation have been developed and used to estimate gestational age (GA) at birth. The most reliable measures of GA are prenatal measures, especially from the first trimester. Postnatal GA measurements tend to be least accurate at the extremes of gestation, that is, in extremely preterm and post-term infants. Observations of measures of neuromaturation in infants born to mothers with pregnancy complications, including intrauterine growth restriction, multiple gestation, and chronic hypertension, have led to the discovery that stressed pregnancies may accelerate fetal pulmonary and CNS maturation. This acceleration of neuromaturation does not occur before 30 weeks' gestation and has a cost with respect to cognitive limitations manifested in childhood. The ability to measure fetal and preterm neuromaturation provides an assessment of neurodevelopmental progress that can be used to reassure parents or identify at risk infants who would benefit from limited comprehensive follow-up and early intervention services. In addition, measures of neuromaturation have the potential to provide insight into mechanisms of CNS injury and recovery, much-needed early feedback in intervention or treatment trials and a measure of early CNS function for research into the relationships between CNS structure and function. © 2005 Wiley-Liss, Inc. MRDD Research Reviews 2005;11:21,33. [source]

Models of white matter injury: Comparison of infectious, hypoxic-ischemic, and excitotoxic insults

DEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 1 2002
Henrik Hagberg
Abstract White matter damage (WMD) in preterm neonates is strongly associated with adverse outcome. The etiology of white matter injury is not known but clinical data suggest that ischemia-reperfusion and/or infection-inflammation are important factors. Furthermore, antenatal infection seems to be an important risk factor for brain injury in term infants. In order to explore the pathophysiological mechanisms of WMD and to better understand how infectious agents may affect the vulnerability of the immature brain to injury, numerous novel animal models have been developed over the past decade. WMD can be induced by antenatal or postnatal administration of microbes (E. coli or Gardnerella vaginalis), virus (border disease virus) or bacterial products (lipopolysaccharide, LPS). Alternatively, various hypoperfusion paradigms or administration of excitatory amino acid receptor agonists (excitotoxicity models) can be used. Irrespective of which insult is utilized, the maturational age of the CNS and choice of species seem critical. Generally, lesions with similarity to human WMD, with respect to distribution and morphological characteristics, are easier to induce in gyrencephalic species (rabbits, dogs, cats and sheep) than in rodents. Recently, however, models have been developed in rats (PND 1,7), using either bilateral carotid occlusion or combined hypoxia-ischemia, that produce predominantly white matter lesions. LPS is the infectious agent most often used to produce WMD in immature dogs, cats, or fetal sheep. The mechanism whereby LPS induces brain injury is not completely understood but involves activation of toll-like receptor 4 on immune cells with initiation of a generalized inflammatory response resulting in systemic hypoglycemia, perturbation of coagulation, cerebral hypoperfusion, and activation of inflammatory cells in the CNS. LPS and umbilical cord occlusion both produce WMD with quite similar distribution in 65% gestational sheep. The morphological appearance is different, however, with a more pronounced infiltration of inflammatory cells into the brain and focal microglia/macrophage ("inflammatory WMD") in response to LPS compared to hypoperfusion evoking a more diffuse microglial response usually devoid of cellular infiltrates ("ischemic WMD"). Furthermore, low doses of LPS that by themselves have no adverse effects in 7-day-old rats (maturation corresponding to the near term human fetus), dramatically increase brain injury to a subsequent hypoxic-ischemic challenge, implicating that bacterial products can sensitize the immature CNS. Contrary to this finding, other bacterial agents like lipoteichoic acid were recently shown to induce tolerance of the immature brain suggesting that the innate immune system may respond differently to various ligands, which needs to be further explored. MRDD Research Reviews 2002;8:30,38. © 2002 Wiley-Liss, Inc. [source]

Neuron-specific expression of atp6v0c2 in zebrafish CNS

DEVELOPMENTAL DYNAMICS, Issue 9 2010
Ah-Young Chung
Abstract Vacuolar ATPase (V-ATPase) is a multi-subunit enzyme that plays an important role in the acidification of a variety of intracellular compartments. ATP6V0C is subunit c of the V0 domain that forms the proteolipid pore of the enzyme. In the present study, we investigated the neuron-specific expression of atp6v0c2, a novel isoform of the V-ATPase c-subunit, during the development of the zebrafish CNS. Zebrafish atp6v0c2 was isolated from a genome-wide analysis of the zebrafish mibta52b mutant designed to identify genes differentially regulated by Notch signaling. Whole-mount in situ hybridization revealed that atp6v0c2 is expressed in a subset of CNS neurons beginning several hours after the emergence of post-mitotic neurons. The ATP6V0C2 protein is co-localized with the presynaptic vesicle marker, SV2, suggesting that it is involved in neurotransmitter storage and/or secretion in neurons. In addition, the loss-of-function experiment suggests that ATP6V0C2 is involved in the control of neuronal excitability. Developmental Dynamics 239:2501,2508, 2010. © 2010 Wiley-Liss, Inc. [source]

Perplexing Pax: From puzzle to paradigm

DEVELOPMENTAL DYNAMICS, Issue 10 2008
Judith A. Blake
Abstract Pax transcription factors are critical for the development of the central nervous system (CNS) where they have a biphasic role, initially dictating CNS regionalization, while later orchestrating differentiation of specific cell subtypes. While a plethora of expression, misexpression, and mutation studies lend support for this argument and clarify the importance of Pax genes in CNS development, less well understood, and more perplexing, is the continued Pax expression in the adult CNS. In this article we explore the mechanism of action of Pax genes in general, and while being cognizant of existing developmental data, we also draw evidence from (1) adult progenitor cells involved in regeneration and tissue maintenance, (2) specific expression patterns in fully differentiated adult cells, and (3) analysis of direct target genes functioning downstream of Pax proteins. From this, we present a more encompassing theory that Pax genes are key regulators of a cell's measured response to a dynamic environment. Developmental Dynamics 237:2791,2803, 2008. © 2008 Wiley-Liss, Inc. [source]

SPARC is expressed by macroglia and microglia in the developing and mature nervous system

DEVELOPMENTAL DYNAMICS, Issue 5 2008
Adele J. Vincent
Abstract SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein that is highly expressed during development, tissue remodeling, and repair. SPARC produced by olfactory ensheathing cells (OECs) can promote axon sprouting in vitro and in vivo. Here, we show that in the developing nervous system of the mouse, SPARC is expressed by radial glia, blood vessels, and other pial-derived structures during embryogenesis and postnatal development. The rostral migratory stream contains SPARC that becomes progressively restricted to the SVZ in adulthood. In the adult CNS, SPARC is enriched in specialized radial glial derivatives (Müller and Bergmann glia), microglia, and brainstem astrocytes. The peripheral glia, Schwann cells, and OECs express SPARC throughout development and in maturity, although it appears to be down-regulated with maturation. These data suggest that SPARC may be expressed by glia in a spatiotemporal manner consistent with a role in cell migration, neurogenesis, synaptic plasticity, and angiogenesis. Developmental Dynamics 237:1449-1462, 2008. © 2008 Wiley-Liss, Inc. [source]

The commonly used marker ELAV is transiently expressed in neuroblasts and glial cells in the Drosophila embryonic CNS

DEVELOPMENTAL DYNAMICS, Issue 12 2007
Christian Berger
Abstract Glial cells in the Drosophila embryonic nervous system can be monitored with the marker Reversed-polarity (Repo), whereas neurons lack Repo and express the RNA-binding protein ELAV (Embryonic Lethal, Abnormal Vision). Since the first description of the ELAV protein distribution in 1991 (Robinow and White), it is believed that ELAV is an exclusive neuronal and postmitotic marker. Looking at ELAV expression, we unexpectedly observed that, in addition to neurons, ELAV is transiently expressed in embryonic glial cells. Furthermore, it is transiently present in the proliferating longitudinal glioblast, and it is transcribed in embryonic neuroblasts. Likewise, elav -Gal4 lines, which are generally used as postmitotic neuronal driver lines, show expression in neural progenitor cells and nearly all embryonic glial cells. Thus, in the embryo, elav can no longer be considered an exclusive marker or driver for postmitotic neurons. elav loss-of-function mutants show no obvious effects on the number and pattern of embryonic glia. Developmental Dynamics 236:3562,3568, 2007. © 2007 Wiley-Liss, Inc. [source]

Retinoic acid, a regeneration-inducing molecule

DEVELOPMENTAL DYNAMICS, Issue 2 2003
Malcolm Maden
Abstract Retinoic acid (RA) is the biologically active metabolite of vitamin A. It is a low molecular weight, lipophilic molecule that acts on the nucleus to induce gene transcription. In amphibians and mammals, it induces the regeneration of several tissues and organs and these examples are reviewed here. RA induces the "super-regeneration" of organs that can already regenerate such as the urodele amphibian limb by respecifying positional information in the limb. In organs that cannot normally regenerate such as the adult mammalian lung, RA induces the complete regeneration of alveoli that have been destroyed by various noxious treatments. In the mammalian central nervous system (CNS), which is another tissue that cannot regenerate, RA does not induce neurite outgrowth as it does in the embryonic CNS, because one of the retinoic acid receptors, RAR,2, is not up-regulated. When RAR,2 is transfected into the adult spinal cord in vitro, then neurite outgrowth is stimulated. In all these cases, RA is required for the development of the organ, in the first place suggesting that the same gene pathways are likely to be used for both development and regeneration. This suggestion, therefore, might serve as a strategy for identifying potential tissue or organ targets that have the capacity to be stimulated to regenerate. Developmental Dynamics 226:237,244, 2003.© 2003 Wiley-Liss, Inc. [source]

Drosophila NAB (dNAB) is an orphan transcriptional co-repressor required for correct CNS and eye development

DEVELOPMENTAL DYNAMICS, Issue 1 2003
Mark Clements
Abstract The mammalian NAB proteins have been identified previously as potent co-repressors of the EGR family of zinc finger transcription factors. Drosophila NAB (dNAB), like its mammalian counterparts, binds EGR1 and represses EGR1-mediated transcriptional activation from a synthetic promoter. In contrast, dNAB does not bind the Drosophila EGR-related protein klumpfuss. dnab RNA is expressed exclusively in a subset of neuroblasts in the embryonic and larval central nervous system (CNS), as well as in several larval imaginal disc tissues. Here, we describe the creation of targeted deletion mutations in the dnab gene and the identification of additional, EMS-induced dnab mutations by genetic complementation analysis. Null alleles in dnab cause larval locomotion defects and early larval lethality (L1,L2). A putative hypomorphic allele in dnab instead causes early adult lethality due to severe locomotion defects. In the dnab -/- CNS, axon outgrowth/guidance and glial development appear normal; however, a subset of eve+ neurons forms in reduced numbers. In addition, mosaic analysis in the eye reveals that dnab -/- clones are either very small or absent. Similarly, dNAB overexpression in the eye causes eyes to be very small with few ommatidia. These dramatic eye-specific phenotypes will prove useful for enhancer/suppressor screens to identify dnab-interacting genes. © 2002 Wiley-Liss, Inc. [source]

Friedrich Nietzsche's mental illness , general paralysis of the insane vs. frontotemporal dementia

ACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2006
M. Orth
Objective:, For a long time it was thought that Nietzsche suffered from general paralysis of the insane (GPI). However, this diagnosis has been questioned recently, and alternative diagnoses have been proposed. Method:, We have charted Friedrich Nietzsche's final fatal illness, and viewed the differential diagnosis in the light of recent neurological understandings of dementia syndromes. Results:, It is unclear that Nietzsche ever had syphilis. He lacked progressive motor and other neurological features of a progressive syphilitic central nervous system (CNS) infection and lived at least 12 years following the onset of his CNS signs, which would be extremely rare for patients with untreated GPI. Finally, his flourish of productivity in 1888 would be quite uncharacteristic of GPI, but in keeping with reports of burgeoning creativity at some point in the progression of frontotemporal dementia (FTD). Conclusion:, We suggest that Nietzsche did not have GPI, but died from a chronic dementia, namely FTD. [source]

The migratory behavior of immature enteric neurons

DEVELOPMENTAL NEUROBIOLOGY, Issue 1 2009
M.M. Hao
Abstract While they are migrating caudally along the developing gut, around 10%,20% of enteric neural crest-derived cells start to express pan-neuronal markers and tyrosine hydroxylase (TH). We used explants of gut from embryonic TH-green fluorescence protein (GFP) mice and time-lapse microscopy to examine whether these immature enteric neurons migrate and their mode of migration. In the gut of E10.5 and E11.5 TH-GFP mice, around 50% of immature enteric neurons (GFP+ cells) migrated, with an average speed of around 15 ,m/h. This is slower than the speed at which the population of enteric neural crest-derived cells advances along the developing gut, and hence neuronal differentiation seems to slow, but not necessarily halt, the caudal migration of enteric neural crest cells. Most migrating immature enteric neurons migrated caudally by extending a long-leading process followed by translocation of the cell body. This mode of migration is different from that of non-neuronal enteric neural crest-derived cells and neural crest cells in other locations, but resembles that of migrating neurons in many regions of the developing central nervous system (CNS). In migrating immature enteric neurons, a swelling often preceded the movement of the nucleus in the direction of the leading process. However, the centrosomal marker, pericentrin, was not localized to either the leading process or swelling. This seems to be the first detailed report of neuronal migration in the developing mammalian peripheral nervous system. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2009. [source]

Nitric oxide regulates axonal regeneration in an insect embryonic CNS

DEVELOPMENTAL NEUROBIOLOGY, Issue 3 2008
Michael Stern
Abstract In higher vertebrates, the central nervous system (CNS) is unable to regenerate after injury, at least partially because of growth-inhibiting factors. Invertebrates lack many of these negative regulators, allowing us to study the positive factors in isolation. One possible molecular player in neuronal regeneration is the nitric oxide (NO),cyclic guanosine-monophosphate (cGMP) transduction pathway which is known to regulate axonal growth and neural migration. Here, we present an experimental model in which we study the effect of NO on CNS regeneration in flat-fillet locust embryo preparations in culture after crushing the connectives between abdominal ganglia. Using whole-mount immunofluorescence, we examine the morphology of identified serotonergic neurons, which send a total of four axons through these connectives. After injury, these axons grow out again and reach the neighboring ganglion within 4 days in culture. We quantify the number of regenerating axons within this period and test the effect of drugs that interfere with NO action. Application of exogenous NO or cGMP promotes axonal regeneration, whereas scavenging NO or inhibition of soluble guanylyl cyclase delays regeneration, an effect that can be rescued by application of external cGMP. NO-induced cGMP immunostaining confirms the serotonergic neurons as direct targets for NO. Putative sources of NO are resolved using the NADPH-diaphorase technique. We conclude that NO/cGMP promotes outgrowth of regenerating axons in an insect embryo, and that such embryo-culture systems are useful tools for studying CNS regeneration. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2008 [source]

The zebrafish ennui behavioral mutation disrupts acetylcholine receptor localization and motor axon stability

DEVELOPMENTAL NEUROBIOLOGY, Issue 1 2008
Louis Saint-Amant
Abstract The zebrafish ennui mutation was identified from a mutagenesis screen for defects in early behavior. Homozygous ennui embryos swam more slowly than wild-type siblings but normal swimming recovered during larval stages and homozygous mutants survived until adulthood. Electrophysiological recordings from motoneurons and muscles suggested that the motor output of the CNS following mechanosensory stimulation was normal in ennui, but the synaptic currents at the neuromuscular junction were significantly reduced. Analysis of acetylcholine receptors (AChRs) in ennui muscles showed a marked reduction in the size of synaptic clusters and their aberrant localization at the myotome segment borders of fast twitch muscle. Prepatterned, nerve-independent AChR clusters appeared normal in mutant embryos and dispersed upon outgrowth of motor axons onto the muscles. Genetic mosaic analysis showed that ennui is required cell autonomously in muscle fibers for normal synaptic localization of AChRs. Furthermore, exogenous agrin failed to induce AChR aggregation, suggesting that ennui is crucial for agrin function. Finally, motor axons branched more extensively in ennui fast twitch muscles especially in the region of the myotome borders. These results suggest that ennui is important for nerve-dependent AChR clustering and the stability of axon growth. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2008 [source]

Developmental characteristics of AMPA receptors in chick lumbar motoneurons

DEVELOPMENTAL NEUROBIOLOGY, Issue 11 2007
Xianglian Ni
Abstract Ca2+ fluxes through ionotropic glutamate receptors regulate a variety of developmental processes, including neurite outgrowth and naturally occurring cell death. In the CNS, NMDA receptors were originally thought to be the sole source of Ca2+ influx through glutamate receptors; however, AMPA receptors also allow a significant influx of Ca2+ ions. The Ca2+ permeability of AMPA receptors is regulated by the insertion of one or more edited GluR2 subunits. In this study, we tested the possibility that changes in GluR2 expression regulate the Ca2+ permeability of AMPA receptors during a critical period of neuronal development in chick lumbar motoneurons. GluR2 expression is absent between embryonic day (E) 5 and E7, but increases significantly by E8 in the chick ventral spinal cord. Increased GluR2 protein expression is correlated with parallel changes in GluR2 mRNA in the motoneuron pool. Electrophysiological recordings of kainate-evoked currents indicate a significant reduction in the Ca2+ -permeability of AMPA receptors between E6 and E11. Kainate-evoked currents were sensitive to the AMPA receptor blocker GYKI 52466. Application of AMPA or kainate generates a significant increase in the intracellular Ca2+ concentration in E6 spinal motoneurons, but generates a small response in older neurons. Changes in the Ca2+ -permeability of AMPA receptors are not mediated by age-dependent changes in the editing pattern of GluR2 subunits. These findings raise the possibility that Ca2+ influx through Ca2+ -permeable AMPA receptors plays an important role during early embryonic development in chick spinal motoneurons. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007 [source]

Combinatorial treatments for promoting axon regeneration in the CNS: Strategies for overcoming inhibitory signals and activating neurons' intrinsic growth state

DEVELOPMENTAL NEUROBIOLOGY, Issue 9 2007
Larry I. Benowitz
Abstract In general, neurons in the mature mammalian central nervous system (CNS) are unable to regenerate injured axons, and neurons that remain uninjured are unable to form novel connections that might compensate for ones that have been lost. As a result of this, victims of CNS injury, stroke, or certain neurodegenerative diseases are unable to fully recover sensory, motor, cognitive, or autonomic functions. Regenerative failure is related to a host of inhibitory signals associated with the extracellular environment and with the generally low intrinsic potential of mature CNS neurons to regenerate. Most research to date has focused on extrinsic factors, particularly the identification of inhibitory proteins associated with myelin, the perineuronal net, glial cells, and the scar that forms at an injury site. However, attempts to overcome these inhibitors have resulted in relatively limited amounts of CNS regeneration. Using the optic nerve as a model system, we show that with appropriate stimulation, mature neurons can revert to an active growth state and that when this occurs, the effects of overcoming inhibitory signals are enhanced dramatically. Similar conclusions are emerging from studies in other systems, pointing to a need to consider combinatorial treatments in the clinical setting. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007 [source]

Regulation of FGF10 by POU transcription factor Brn3a in the developing trigeminal ganglion

DEVELOPMENTAL NEUROBIOLOGY, Issue 10 2006
Eric Cox
Abstract The POU-domain transcription factor Brn3a is expressed in specific neurons of the caudal CNS and peripheral sensory nervous system. The sensory neurons of mice lacking Brn3a exhibit marked defects in axon growth and extensive apoptosis in lategestation. Here we show that expression of thedevelopmental regulator FGF10 is approximately 35-fold increased in the developing trigeminal ganglia of Brn3a-null mice. In order to determine whether FGF10 regulates other changes in gene expression observed in Brn3a knock-out ganglia, we have used a sensory-specific enhancer to over-express FGF10 in transgenic mice. Microarray analysis of trigeminal ganglia from individual transgenic founders effectivelyexcludes the cell-autonomous activity of FGF10 as a mechanism for mediating the downstream effects of the loss of Brn3a, probably because developing sensory neurons lack the appropriate type of FGF receptor. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source]

Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cells

DEVELOPMENTAL NEUROBIOLOGY, Issue 6 2006
Hagit Cohen
Abstract Peripheral cellular immunity was recently shown to play a critical role in brain plasticity and performance. The antigenic specificity of the participating T cells, however, was not investigated, and nor was their relevance to psychological stress. Here we show, using a mouse model, that adaptive immunity mitigates maladaptation to the acute psychological stress known to trigger abnormal behaviors reminiscent of human post-traumatic stress disorder. Assessment of behavioral adaptation (measured by the acoustic startle response and avoidance behavior) in mice after their exposure to predator odor revealed that maladaptation was several times more prevalent in T cell-deficient mice than in their wild-type counterparts. A single population of T cells reactive to central nervous system (CNS)-associated self-protein was sufficient to endow immune-deficient mice with the ability to withstand the psychological stress. Naturally occurring CD4+CD25+ regulatory T cells were found to suppress this endogenous anti-stress attribute. These findings suggest that T cells specific to abundantly expressed CNS antigens are responsible for brain tissue homeostasis and help the individual to cope with stressful life episodes. They might also point the way to development of immune-based therapies for mental disorders, based either on up-regulation of T cells that partially cross-react with self-antigens or on weakening of the activity of regulatory T cells. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source]

Cell-type-specific limitation on in vivo serotonin storage following ectopic expression of the Drosophila serotonin transporter, dSERT

DEVELOPMENTAL NEUROBIOLOGY, Issue 5 2006
Sang Ki Park
Abstract The synaptic machinery for neurotransmitter storage is cell-type specific. Although most elements of biosynthesis and transport have been identified, it remains unclear whether additional factors may be required to maintain this specificity. The Drosophila serotonin transporter (dSERT) is normally expressed exclusively in serotonin (5-HT) neurons in the CNS. Here we examine the effects of ectopic transcriptional expression of dSERT in the Drosophila larval CNS. We find a surprising limitation on 5-HT storage following ectopic expression of dSERT and green fluorescence protein-tagged dSERT (GFP-dSERT). When dSERT transcription is driven ectopically in the CNS, 5-HT is detectable only in 5-HT, dopamine (DA), and a very limited number of additional neurons. Addition of exogenous 5-HT does not dramatically broaden neuronal storage sites, so this limitation is only partly due to restricted intercellular diffusion of 5-HT. Furthermore, this limitation is not due to gross mislocalization of dSERT, because cells lacking or containing 5-HT show similar levels and subcellular distribution of GFP-dSERT protein, nor is it due to lack of the vesicular transporter, dVMAT. These data suggest that a small number of neurons selectively express factor(s) required for 5-HT storage, and potentially for function of dSERT. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source]

Widely distributed Drosophila G-protein-coupled receptor (CG7887) is activated by endogenous tachykinin-related peptides

DEVELOPMENTAL NEUROBIOLOGY, Issue 1 2006
Ryan T. Birse
Abstract Neuropeptides related to vertebrate tachykinins have been identified in Drosophila. Two Drosophila G-protein-coupled receptors (GPCRs), designated NKD (CG6515) and DTKR (CG7887), cloned earlier, display sequence similarities to mammalian tachykinin receptors. However, they were not characterized with the endogenous Drosophila tachykinins (DTKs). The present study characterizes one of these receptors, DTKR. We determined that HEK-293 cells transfected with DTKR displayed dose-dependent increases in both intracellular calcium and cyclic AMP levels in response to the different DTK peptides. DTK peptides also induced internalization of DTKR-green fluorescent protein (GFP) fusion constructs in HEK-293 cells. We generated specific antireceptor antisera and showed that DTKR is widely distributed in the adult brain and more scarcely in the larval CNS. The distribution of the receptor in brain neuropils corresponds well with the distribution of its ligands, the DTKs. Our findings suggest that DTKR is a DTK receptor in Drosophila and that this ligand-receptor system plays multiple functional roles. © 2005 Wiley Periodicals, Inc. J Neurobiol, 2006 [source]

Methanol exposure interferes with morphological cell movements in the Drosophila embryo and causes increased apoptosis in the CNS

DEVELOPMENTAL NEUROBIOLOGY, Issue 3 2004
Dervla M. Mellerick
Abstract Despite the significant contributions of tissue culture and bacterial models to toxicology, whole animal models for developmental neurotoxins are limited in availability and ease of experimentation. Because Drosophila is a well understood model for embryonic development that is highly accessible, we asked whether it could be used to study methanol developmental neurotoxicity. In the presence of 4% methanol, approximately 35% of embryos die and methanol exposure leads to severe CNS defects in about half those embryos, where the longitudinal connectives are dorsally displaced and commissure formation is severely reduced. In addition, a range of morphological defects in other germ layers is seen, and cell movement is adversely affected by methanol exposure. Although we did not find any evidence to suggest that methanol exposure affects the capacity of neuroblasts to divide or induces inappropriate apoptosis in these cells, in the CNS of germ band retracted embryos, the number of apoptotic nuclei is significantly increased in methanol-exposed embryos in comparison to controls, particularly in and adjacent to the ventral midline. Apoptosis contributes significantly to methanol neurotoxicity because embryos lacking the cell death genes grim, hid, and reaper have milder CNS defects resulting from methanol exposure than wild-type embryos. Our data suggest that when neurons and glia are severely adversely affected by methanol exposure, the damaged cells are cleared by apoptosis, leading to embryonic death. Thus, the Drosophila embryo may prove useful in identifying and unraveling mechanistic aspects of developmental neurotoxicity, specifically in relation to methanol toxicity. © 2004 Wiley Periodicals, Inc. J Neurobiol 60: 308,318, 2004 [source]

A diffusible signal attracts olfactory sensory axons toward their target in the developing brain of the moth

DEVELOPMENTAL NEUROBIOLOGY, Issue 1 2003
Lynne A. Oland
Abstract The signals that olfactory receptor axons use to navigate to their target in the CNS are still not well understood. In the moth Manduca sexta, the primary olfactory pathway develops postembryonically, and the receptor axons navigate from an experimentally accessible sensory epithelium to the brain along a pathway long enough for detailed study of regions in which axon behavior changes. The current experiments ask whether diffusible factors contribute to receptor axon guidance. Explants were made from the antennal receptor epithelium and co-cultured in a collagen gel matrix with slices of various regions of the brain. Receptor axons were attracted toward the central regions of the brain, including the protocerebrum and antennal lobe. Receptor axons growing into a slice of the most proximal region of the antennal nerve, where axon sorting normally occurs, showed no directional preference. When the antennal lobe was included in the slice, the receptor axons entering the sorting region grew directly toward the antennal lobe. Taken together with the previous in vivo experiments, the current results suggest that an attractive diffusible factor can serve as one cue to direct misrouted olfactory receptor axons toward the medial regions of the brain, where local cues guide them to the antennal lobe. They also suggest that under normal circumstances, in which the receptor axons follow a pre-existing pupal nerve to the antennal lobe, the diffusible factor emanating from the lobe acts in parallel and at short range to maintain the fidelity of the path into the antennal lobe. © 2003 Wiley Periodicals, Inc. J Neurobiol 56: 24,40, 2003 [source]

In vivo dynamics of CNS sensory arbor formation: A time-lapse study in the embryonic leech

DEVELOPMENTAL NEUROBIOLOGY, Issue 1 2003
Michael W. Baker
Abstract In the embryo of the leech Hirudo medicinalis, afferent projections of peripheral sensory neurons travel along common nerve tracts to the CNS, where they defasciculate, branch, and arborize into separate, modality-specific synaptic laminae. Previous studies have shown that this process requires, at least in part, the constitutive and then modality-specific glycosylations of tractin, a leech L1 homologue. We report here on the dynamics of growth of these projections as obtained by examining the morphology of single growing dye-filled sensory afferents as a function of time. Using 2-photon laser-scanning microscopy of the intact developing embryo, we obtained images of individual sensory projections at 3 to 30 min intervals, over several hours of growth, and at different stages of development. The time-lapse series of images revealed a highly dynamic and maturation-state-dependent pattern of growth. Upon entering the CNS, the growth cone-tipped primary axon sprouted numerous long filopodial processes, many of which appeared to undergo repeated cycles of extension and retraction. The growth cone was transformed into a sensory arbor through the formation of secondary branches that extended within the ganglionic neuropil along the anterior-posterior axis of the CNS. Numerous tertiary and quaternary processes grew from these branches and also displayed cycles of extension and retraction. The motility of these higher-order branches changed with age, with younger afferents displaying higher densities and greater motility than older, more mature sensory arbors. Finally, coincident with a reduction in higher order projections was the appearance of concavolar structures on the secondary processes. Rows of these indentations suggest the formation of presynaptic en-passant specializations accompanying the developmental onset of synapse formation. © 2003 Wiley Periodicals, Inc. J Neurobiol 56: 41,53, 2003 [source]