Glial ensheathment of peripheral axons inDrosophila

The ensheathment of neurons and their axons creates an ion-sensitive microenvironment that allows rapid conduction of nerve impulses. One of the fundamental questions about axonal ensheathment is how insulating glial cells wrap around axons. The mechanisms that underlie insulation of axons in invertebrates and vertebrates are not fully understood. In the present article we address cellular aspects of axonal ensheathment in Drosophila by taking advantage of glial mutants that illustrate a range of phenotypic defects including ensheathment of axons. From the findings of these mutant studies, we summarize that loss of glial cells, defects in glial membrane wrapping, failure of glial migration, and loss of specialized ladderlike septate junctions between ensheathing glial membranes result in axon-glial functional defects. These studies provide a broad perspective on glial ensheathment of axons in Drosophila and key insights into the anatomical and cellular aspects of axonal insulation. Given the powerful genetic approaches available in Drosophila, the axonal ensheathment process can be dissected in great detail to reveal the fundamental principles of ensheathment. These observations will be relevant to understanding the very similar processes in vertebrates, where defects in glial cell functions lead to devastating neurological diseases

Cytoskeletal transition at the paranodes: the Achilles' heel of myelinated axons

Myelination organizes axons into distinct domains that allow nerve impulses to propagate in a saltatory manner. The edges of the myelin sheath are sealed at the paranodes by axon–glial junctions that have a crucial role in organizing the axonal cytoskeleton. Here we propose a model in which the myelinated axons depend on the axon–glial junctions to stabilize the cytoskeletal transition at the paranodes. Thus paranodal regions are likely to be particularly susceptible to damage induced by demyelinating diseases such as multiple sclerosis

Chromatid Segregation at Anaphase Requires the barren Product, a Novel Chromosome-Associated Protein That Interacts with Topoisomerase II

AbstractWe have isolated a Drosophila gene, barren (barr), required for sister-chromatid segregation in mitosis. barr encodes a novel protein that is present in proliferating cells and has homologs in yeast and human. Mitotic defects in barr embryos become apparent during cycle 16, resulting in a loss of PNS and CNS neurons. Centromeres move apart at the metaphase–anaphase transition and Cyclin B is degraded, but sister chromatids remain connected, resulting in chromatin bridging. This phenotype is similar to that described in TOP2 mutants in yeast. Barren protein localizes to chromatin throughout mitosis. Colocalization and biochemical experiments indicate that Barren associates with Topoisomerase II throughout mitosis and alters the activity of Topoisomerase II. We propose that this association is required for proper chromosomal segregation by facilitating the decatenation of chromatids at anaphase

Relationship between the levels of Serum Thyroid Hormones and the Risk of Breast Cancer

Breast cancer is still one of the leading causes of cancer death in women, but there has been a sustained decline in mortality rates over the last decades the relationship between breast cancer and thyroid diseases is controversial many works have been done in past also. The relation between autoimmune and non-autoimmune thyroid diseases has been investigated in patients with breast cancer and age-matched control individuals without breast or thyroid disease. Determination of serum thyroid hormone and antibody levels was done in 100 breast cancer patients and 75 control individuals. The mean values for thyroid hormones and anti-thyroid peroxidase antibodies were significantly higher in breast cancer patients than in control individuals. Our results indicate an increased prevalence of autoimmune and non-autoimmune thyroid diseases in breast cancer patients. Keywords: breast, cancer, autoimmune thyroid diseases

Axonal Ensheathment and Intercellular Barrier Formation in Drosophila

Glial cells are critical players in every major aspect of nervous system development, function, and disease. Other than their traditional supportive role, glial cells perform a variety of important functions such as myelination, synapse formation and plasticity, and establishment of blood–brain and blood–nerve barriers in the nervous system. Recent studies highlight the striking functional similarities between Drosophila and vertebrate glia. In both systems, glial cells play an essential role in neural ensheathment thereby isolating the nervous system and help to create a local ionic microenvironment for conduction of nerve impulses. Here, we review the anatomical aspects and the molecular players that underlie ensheathment during different stages of nervous system development in Drosophila and how these processes lead to the organization of neuroglial junctions. We also discuss some key aspects of the invertebrate axonal ensheathment and junctional organization with that of vertebrate myelination and axon–glial interactions. Finally, we highlight the importance of intercellular junctions in barrier formation in various cellular contexts in Drosophila. We speculate that unraveling the genetic and molecular mechanisms of ensheathment across species might provide key insights into human myelin-related disorders and help in designing therapeutic interventions

Localization of the paranodal protein Caspr in the mammalian retina

Purpose: The retina has the demanding task of encoding all aspects of the visual scene within the space of one fixation period lasting only a few hundred milliseconds. To accomplish this feat, information is encoded in specialized parallel channels and passed on to numerous central nuclei via the optic nerve. These parallel channels achieve specialization in at least three ways: the synaptic networks in which they participate, the neurotransmitter receptors expressed and the types and locations of ion channels or transporters used. Subcellular localization of receptors, channels and transporters is made yet more complex in the retina by the double duty many retinal processes serve. In the present work, we show that the protein Caspr (Contactin Associated Protein), best known for its critical role in the localization of voltage-gated ion channels at the nodes of Ranvier, is present in several types of retinal neurons including amacrine, bipolar, horizontal, and ganglion cells. Methods: Using standard double label immunofluorescence protocols, we characterized the pattern of Caspr expression in the rodent retina. Results: Caspr labeling was observed through much of the retina, including horizontal, bipolar, amacrine, and ganglion cells. Among amacrine cells, Caspr was observed in AII amacrine cells through co-localization with Parvalbumin and Disabled-1 in rat and mouse retinas, respectively. An additional amacrine cell type containing Calretinin also co-localized with Caspr, but did not co-localize with choline-acetyltransferase. Nearly all cells in the ganglion cell layer contain Caspr, including both displaced amacrine and ganglion cells. In the outer retina, Caspr was co-localized with PKC labeling in rod bipolar cell dendrites. In addition, Caspr labeling was found inside syntaxin-4 'sandwiches' in the outer plexiform layer, most likely indicating its presence in cone bipolar cell dendrites. Finally, Caspr was co-localized in segments of horizontal cell dendrites labeled with Calbindin-D28k. Conclusions: Caspr is best known for its role in organizing the localization of different voltage-gated ion channels in and around nodes of Ranvier. As neuronal processes in the retina often play a dual role involving both input and output, it is possible that the localization of Caspr in the retina will help us decipher the way retinal cells localize ion channels in their processes to increase computational capacity

Disrupted axo-glial junctions result in accumulation of abnormal mitochondria at nodes of Ranvier

Mitochondria and other membranous organelles are frequently enriched in the nodes and paranodes of peripheral myelinated axons, particularly those of large caliber. The physiologic role(s) of this organelle enrichment and the rheologic factors that regulate it are not well understood. Previous studies suggest that axonal transport of organelles across the nodal/paranodal region is locally regulated. In this study, we have examined the ultrastructure of myelinated axons in the sciatic nerves of mice deficient in the contactin-associated protein (Caspr), an integral junctional component. These mice, which lack the normal septate-like junctions that promote attachment of the glial (paranodal) loops to the axon, contain aberrant mitochondria in their nodal/paranodal regions. These mitochondria are typically large and swollen and occupy prominent varicosities of the nodal axolemma. In contrast, mitochondria located outside the nodal/paranodal regions of the myelinated axons appear normal. These findings suggest that paranodal junctions regulate mitochondrial transport and function in the axoplasm of the nodal/paranodal region of myelinated axons of peripheral nerves. They further implicate the paranodal junctions in playing a role, either directly or indirectly, in the local regulation of energy metabolism in the nodal region

Studies on the Composition, Distribution and Detection of Dark Matter in the Universe

N

Organization and maintenance of molecular domains in myelinated axons

Over a century ago, Ramon y Cajal first proposed the idea of a directionality involved in nerve conduction and neuronal communication. Decades later, it was discovered that myelin, produced by glial cells, insulated axons with periodic breaks where nodes of Ranvier (nodes) form to allow for saltatory conduction. In the peripheral nervous system (PNS), Schwann cells are the glia that can either individually myelinate the axon from one neuron or ensheath axons of many neurons. In the central nervous system (CNS), oligodendrocytes are the glia that myelinate axons from different neurons. Review of more recent studies revealed that this myelination created polarized domains adjacent to the nodes. However, the molecular mechanisms responsible for the organization of axonal domains are only now beginning to be elucidated. The molecular domains in myelinated axons include the axon initial segment (AIS), where various ion channels are clustered and action potentials are initiated; the node, where sodium channels are clustered and action potentials are propagated; the paranode, where myelin loops contact with the axolemma; the juxtaparanode (JXP), where delayed-rectifier potassium channels are clustered; and the internode, where myelin is compactly wrapped. Each domain contains a unique subset of proteins critical for the domain’s function. However, the roles of these proteins in axonal domain organization are not fully understood. In this review, we highlight recent advances on the molecular nature and functions of some of the components of each axonal domain and their roles in axonal domain organization and maintenance for proper neuronal communication

Drosophila Ringmaker regulates microtubule stabilization and axonal extension during embryonic development

Axonal growth and targeting are fundamental to the organization of the nervous system, and require active engagement of the cytoskeleton. Polymerization and stabilization of axonal microtubules is central to axonal growth and maturation of neuronal connectivity. Studies have suggested that members of the tubulin polymerization promoting protein (TPPP, also known as P25α) family are involved in cellular process extension. However, no in vivo knockout data exists regarding its role in axonal growth during development. Here, we report the characterization of Ringmaker (Ringer; CG45057), the only Drosophila homolog of long p25α proteins. Immunohistochemical analyses indicate that Ringer expression is dynamically regulated in the embryonic central nervous system (CNS). ringer-null mutants show cell misplacement, and errors in axonal extension and targeting. Ultrastructural examination of ringer mutants revealed defective microtubule morphology and organization. Primary neuronal cultures of ringer mutants exhibit defective axonal extension, and Ringer expression in cells induced microtubule stabilization and bundling into rings. In vitro assays showed that Ringer directly affects tubulin, and promotes microtubule bundling and polymerization. Together, our studies uncover an essential function of Ringer in axonal extension and targeting through proper microtubule organization