Generating neuronal diversity in the Drosophila central nervous system

Generating diverse neurons in the central nervous system involves three major steps. First, heterogeneous neural progenitors are specified by positional cues at early embryonic stages. Second, neural progenitors sequentially produce neurons or intermediate precursors that acquire different temporal identities based on their birth-order. Third, sister neurons produced during asymmetrical terminal mitoses are given distinct fates. Determining the molecular mechanisms underlying each of these three steps of cellular diversification will unravel brain development and evolution. Drosophila has a relatively simple and tractable CNS, and previous studies on Drosophila CNS development have greatly advanced our understanding of neuron fate specification. Here we review those studies and discuss how the lessons we have learned from fly teach us the process of neuronal diversification in general.     

Antigen-presenting cell diversity for T cell reactivation in central nervous system autoimmunity

Autoreactive T cells are considered the major culprits in the pathogenesis of many autoimmune diseases like multiple sclerosis (MS). Upon activation in the lymphoid organs, autoreactive T cells migrate towards the central nervous system (CNS) and target the myelin sheath-forming oligodendrocytes, resulting in detrimental neurological symptoms. Despite the availability of extensively studied systems like the experimental autoimmune encephalomyelitis (EAE) model, our understanding of this disease and the underlying pathogenesis is still elusive. One vividly discussed subject represents the T cell reactivation in the CNS. In order to exert their effector functions in the CNS, autoreactive T cells must encounter antigen-presenting cells (APCs). This interaction provides an antigen-restricted stimulus in the context of major histocompatibility complex class II (MHC-II) and other co-stimulatory molecules. Peripherally derived dendritic cells (DCs), B cells, border-associated macrophages (BAM), CNS-resident microglia, and astrocytes have the capacity to express molecules required for antigen presentation under inflammatory conditions. Also, endothelial cells can fulfill these prerequisites in certain situations. Which of these cells in fact act as APCs for T cell reactivation and to which extent they can exert this function has been studied intensively, but unfortunately with no firm conclusion. In this review, we will summarize the findings that support or question the antigen presenting capacities of the mentioned cell types of CNS-localized T cell reactivation.     

Generating neuronal diversity in the Drosophila central nervous system: a view from the ganglion mother cells.

The generation of cellular diversity in the developing embryonic central nervous system of Drosophila melanogaster requires the precise orchestration of several convergent molecular and cellular mechanisms. Most reviews have focused on the formation and specification of neuroblasts (NBs), the putative neural stem cell in the Drosophila central nervous system. NBs divide asymmetrically to regenerate themselves and produce a secondary precursor cell called a ganglion mother cell (GMC), which divides to produce neurons and glia. Historically, our understanding of GMC specification has arisen from work involving asymmetric localization of intrinsic factors in the NB and GMC. However, recent information on NB lineages has revealed additional intrinsic factors that specify general and specific GMC fates. This review addresses what has been revealed about these intrinsic cues with regard to GMC specification. For example, Prospero, an asymmetrically localized determinant, plays a general role to enable GMC development and to distinguish GMCs from NBs. In contrast, the temporal gene cascade functions within NB lineages to ensure that each GMC in a lineage acquires a different fate. Two different mechanisms used to make the progeny of GMCs different will also be discussed. One is a generic mechanism, regulated by Notch and Numb, that allows sibling cells to adopt different fates. The other mechanism involves genes, such as even-skipped and klumpfuss that specify the fate of individual GMCs. All of these mechanisms converge within a GMC to bestow upon it a unique fate.     

CuZn-SOD promoter-driven expression in the Drosophila central nervous system

The aim of this study was to ascertain the status of CuZn superoxide dismutase (CuZn-SOD) expression in the central nervous system of Drosophila melanogaster. Immunoblot analysis of dissected tissue extracts revealed low levels of the CuZn-SOD protein in adult brains relative to other adult and larval tissues. To explore further this observation, three different reporter constructs containing different elements of the CuZn-SOD promoter domain were used for the generation of transgenic flies. A high level of reporter gene expression occurred during the second wave of neurogenesis (third instar and early pupal stages) in scattered, proliferating neuroblasts (NBs) and in proliferation centers of the optic lobe. In mature, postmitotic neurons, this expression was lower relative to other tissues. In adult flies, at all ages examined, there was little if any detectable reporter gene expression in cells of the central nervous system. These results suggest that one of the key components of the antioxidant defenses, CuZn-SOD, is quite low in postmitotic neural tissue, rendering it particularly susceptible to oxidative damage during aging.     

polyhomeotic: a gene required for the embryonic development of axon pathways in the central nervous system of Drosophila

Hypomorphic alleles of the locus polyhomeotic (ph) produce multiple, homeotic-like transformations in adult flies that mimic dominant mutations in the Antennapedia and Bithorax complexes. Analysis of null alleles of ph has revealed a complex, embryonically lethal phenotype that includes cell death of the ventral epidermis and abnormalities in the patterns of expression of homeotic and segmentation genes. There is also a dramatic alteration in the pattern of axon pathways in the central nervous system, such that the wild-type array of segmentally repeated commissures and connectives is replaced by bundles of axons confined to the hemiganglia of origin. It is possible that this axonal phenotype is the result of loss of neuronal identity caused by abnormal homeotic and segmentation gene expression.     

Doublesex gene expression in the central nervous system of Drosophila melanogaster

Despite several behavior-genetic studies that have suggested roles played by doublesex (dsx) in neural tissues, it has not been demonstrated that the products of this gene are actually present in the central nervous system (CNS). In this report, we describe the cellular, spatial, and temporal expression patterns of dsx gene products in the developing and adult CNS by applying RT-PCR and immunohistochemical procedures. dsx gene products were detected in the CNS of 3rd-instar larvae, pupae, and adults. DSX-immunoreactive signals were observed within the brain and in both the thoracic plus abdominal ganglia of the ventral nerve cord. Most, but not all, cells inferred to contain DSX proteins (by the results of genetic controls for antibody specificity) were further determined to be neurons (by coexpression of a protein that marks such CNS cell types). Temporally varying expression of DSX was most prominently observed in the rapidly metamorphosing early and mid-pupal stages, suggesting that this gene contributes to establishment of sexually dimorphic neuronal structures which subserve adult sexual behaviors. Elements of the spatial and temporal patterns of DSX immunoreactivity also imply that sexually dimorphic dsx expression in certain neuronal clusters within the adult CNS could participate in ongoing operations of the mature nervous system with respect to the courtship behaviors that are affected by dsx mutations.     

Granular cell tumors of the central nervous system of rats.

On the basis of our study of 12 cases of granular cell tumors in the brains of rats of different inbred strains, it seems that granular cell tumors are not rate in the central nervous system of untreated, aging BN/Bi rats. In none were metastases found. Awareness of the occurrence of these tumors in the central nervous system of these rats may stimulate further studies into the cellular origin of granular cell tumors that form in the central nervous system of the rat and might help to elucidate the origin of these tumors in general.     

Clonal organization in the postnatal mouse central nervous system is prefigured in the embryonic neuroepithelium.

We have used the LaacZ clonal method of cell labeling of neuronal ancestors and report that the spatial organization of neuronal cells in the post-natal CNS shares striking similarities to that in the embryonic neuroepithelium, from the spinal cord to the diencephalon. The maintenance of the organization occurs despite massive cell divisions and morphogenetic movements. We deduce that the cellular and architectural organization in the mouse CNS results from a succession of patterns of oriented cell dispersion, a general arrest of cell dispersion in the neuroepithelium, and then well-documented radial neuronal migration. The arrest of cell dispersion in the neuroepithelium is consistent with the possibility that an important part of the cellular and architectural organization of the mature CNS requires conservation of spatial relationship between cells and supports the hypothesis of a transition from global and sparse to local and dense cell interactions occurring early within the neuroepithelium.     

Primary anaplastic large cell lymphoma of the central nervous system.

Central nervous system (CNS) involvement is extremely rare in anaplastic large cell lymphoma (ALCL), and in children only isolated cases have been reported, mainly as secondary CNS involvement. A case of fatal primary ALCL of the brain in a 13-year-old white boy is reported. Magnetic resonance imaging of the brain showed decreased absorption in T1- and T2-weighted image showed a hyperintense signal in the right parietal lobe and 2 masses in the right frontal lobe. A frontal lobe biopsy showed a pleomorphic neoplasm diffusely infiltrating the brain parenchyma and composed of large cells with bizarre, often polylobated or horseshoe-shaped nuclei. Immunohistochemical stains showed diffuse strong positivity for CD30, anaplastic lymphoma kinase protein (ALK-1), p80, leucocyte common antigen, CD45RO (UCHL1), and focal staining for epithelial membrane antigen. Immunostainings for cytokeratins, monocyte-macrophage, and B-cell markers were negative. Epstein-Barr virus latent membrane protein was not detected. To the best of our knowledge, there is only 1 case of primary ALCL of the brain in childhood previously reported in the literature. Before the biopsy, both cases were clinically misdiagnosed as mycobacterial CNS infection. Therefore, primary ALCL should also be included in the differential diagnosis when a mycobacterial CNS infection is suspected in pediatric patients; a careful cytological evaluation of the cerebrospinal fluid or cerebral biopsy are essential for an accurate diagnosis.     

Immune cell traffic control and the central nervous system

That lymphocytes traffic to the central nervous system (CNS) is a relatively new concept. From studies on lymphocyte trafficking to lymphoid tissue and systemic organs, it is known that small lymphocytes recirculate continually from blood to lymphoid tissue and back again to blood, and that lymphocyte activation leads to changes in trafficking patterns with rerouting to areas of antigen deposition. Control of lymphocyte trafficking involves the induction and expression of a series of cell-surface molecules on circulating immune cells and target tissue vasculature. Lymphocyte trafficking into the CNS preferentially involves activated lymphocytes. This may be secondary to elaboration by activated immune cells of cytokines which are capable of stimulating CNS endothelium and may also relate to their production of enzymes which degrade cytoskeletal elements, aiding transmigration. Based upon observations of systemic homing receptors specific for certain organs, the existence of CNS-specific homing receptors with corresponding ligands on CNS vasculature is postulated.     

具有梭形细胞的神经系统肿瘤

中枢神经系统很多肿瘤都以梭形细胞为表型,了解这些肿瘤的病变特点并结合免疫组织化学染色,有助于正确判断肿瘤来源和良恶性.     

The distribution pattern of adrenocorticotropin-like immunoreactivity in the cat central nervous system

The distribution pattern of adrenocorticotropin-like immunoreactivity (ACTH-LI) in cats using the avidin-biotin modification of an immunocytochemical method shows cell bodies containing ACTH-LI in the medial basal hypothalamus, especially in the infundibular nucleus. The fibers from these neurons extended beyond the hypothalamus, into the paraventricular nucleus of the thalamus, rostral amygdala, periaqueductal gray, locus coeruleus, parabrachial nucleus and medial nucleus of the nucleus tractus solitarius. The distribution pattern of the cell bodies and fibers containing ACTH-LI bears several similarities to that seen in rats. The pattern differs from that of rats in the fact that the termination in the amygdala is more extensive and that ACTH-LI was not observed in cell bodies in any location other than the medial basal hypothalamus.     

Embryonic expression pattern of a family of Drosophila proteins that interact with a central nervous system regulatory element

The protein Elf-1 interacts with a cis-acting element that is required specifically for the neuronal expression of the Drosophila dopa decarboxylase gene Ddc. Using protein purified from Drosophila embryos, we raised Elf-1-specific monoclonal antibodies. The expression of Elf-1 during embryogenesis is restricted to nuclei of tissues derived from ectoderm, predominantly the central nervous system (CNS) and the epidermis. Within the CNS, Elf-1 is present in only a small fraction of nuclei, and the pattern of expressing nuclei changes dramatically during development. Elf-1 and Ddc are coexpressed in primary cultures of neural cells. However, we do not detect Elf-1 in Ddc-expressing neurons in vivo, leading to the suggestion that Elf-1 activity is required in vivo for initiation of Ddc expression but not for its maintenance. The antibodies also were used to isolate cDNA clones encoding Elf-1. Alternate forms of Elf-1 mRNA result in at least three protein isoforms.     

Functional AMPA/kainate receptors in human embryonic and foetal central nervous system

Here, functional AMPA/kainate receptors in human embryonic (5.5–7.5 gestational weeks) and foetal (8–10 gestational weeks) central nervous system tissue, shown by the cobalt labeling method, are reported. Specific agonist-induced cobalt incorporation was detected in brainstem and spinal cord cells, even in the youngest embryo studied. T-AMPA or kainate, but also vegetal toxins such as L-BOAA or acromelate, induced accumulation of cobalt. In contrast, no labeling was observed after exposure to KCl or NMDA. Cobalt labeled cells were particularly prominent in motor regions of brainstem and spinal cord. Co-application of the diuretic agent cyclothiazide, a desensitization blocker at AMPA receptors, dramatically increased the number of stained cells, which was particularly obvious in sensory regions, suggesting different receptor properties in motor versus sensory regions. This is the first study providing evidence for functional AMPA/kainate receptors, permeable to divalent cations, in brainstem and spinal cord at an early stage of human central nervous system development. Since many developmental processes are influenced by the modulation of cytosolic calcium, exposure at critical stages of embryogenesis to food or drug substances modifying the activity of AMPA/kainate receptors may alter brain development.     

Oncocytic and granular cell neoplasms of the central nervous system and pituitary gland.

Oncocytic transformation is an infrequent event within the central nervous system and is limited to neoplasms of the choroid plexus, meninges, and pituitary gland. Oncocytic modifications in choroid plexus tumors seem to occur predominantly in adult patients and in the fourth ventricle and do not seem to reflect any particular biological behavior. Meningiomas showing oncocytic differentiation have been recently described and this variant probably behaves more aggressively. Pituitary oncocytomas are regarded as a subtype of null cell adenomas. Oncocytic tumors have a significantly higher risk of progression with a higher recurrence rate after radiotherapy. Oncocytic changes in astrocytic neoplasms are rare. More frequently, astrocytomas can show granular changes that result in neoplasms composed of cells with granular cytoplasm and eccentric nuclei resembling foamy macrophages. Granular cell astrocytomas may mimic non-neoplastic lesions such as cerebral infarction and demyelinating disease. Cells with granular bodies are frequent in pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglion cell tumors. Their presence is considered a useful diagnostic finding to distinguish these low-grade lesions from malignant gliomas. A rare neoplasm is the granular cell tumor of the infundibulum that, when symptomatic, has to be differentiated from pituitary adenomas and other more common lesions of the sellar region.     

Thiamine transport in the central nervous system.

Total thiamine (free thiamine and thiamine phosphates) transport into the cerebrospinal fluid (CSF), brain, and choroid plexus and out of the CSF was measured in rabbits. In vivo, total thiamine transport into CSF, choroid plexus, and brain was saturable. At the normal plasma total thiamine concentration, less than 5% of total thiamine entry into CSF, choroid plexus, and brain was by simple diffusion. The relative turnovers of total thiamine in choroid plexus, whole brain, and CSF were 5, 2, and 14% per h, respectively, when measured by the penetration of 35S-labeled thiamine injected into blood. From the CSF, clearance of [35S]thiamine relative to mannitol was not saturable after the intraventricular injection of various concentrations of thiamine. However, a portion of the [35S]thiamine cleared from the CSF entered brain by a saturable mechanism. In vitro, choroid plexuses, isolated from rabbits and incubated in artificial CSF, accumulated [35S]thiamine against a concentration gradient by an active saturable process that did not depend on pyrophosphorylation of the [35S]thiamine. The [35S]thiamine accumulated within the choroid plexus in vitro was readily released. These results were interpreted as showing that the entry of total thiamine into the brain and CSF from blood is regulated by a saturable transport system, and that the locus of this system may be, in part, in the choroid plexus.     

Folate transport in the central nervous system.

Methyltetrahydrofolic acid or folic acid was infused intravenously at a constant rate into conscious untreated or methotrexate-pretreated rabbits. After 150 min, at equivalent plasma concentrations, folic acid or methyltetrahydrofolic acid readily entered the cerebrospinal fluid and probably brain by a saturable transport system. In contrast, after intraventricular injections, folic acid but not methyltetrahydrofolic acid was cleared from cerebrospinal fluid to blood by a saturable system. Intraventribular injection of folic acid at concentrations that saturated folic acid clearance from cerebrospinal fluid did not affect the transport of methyltetrahydrofolic acid from blood into cerebrospinal fluid. These results suggest that the transport system for mehtyltetrahydrofolic acid, which is about half-saturated at normal plasma concentrations, helps maintain the cerebrospinal fluid and probably brain methyltetrahydrofolic acid concentrations within relatively narrow limits. Moreover, folic acid, which the brain cannot utilize, is transported from cerebrospinal fluid. A possible locus for the systems that transport folic acid from and methyltetrahydrofolic acid into the cerebrospinal fluid is the choroid plexus.