scholarly journals Defective cortex glia plasma membrane structure underlies light-induced epilepsy in cpes mutants

2018 ◽  
Vol 115 (38) ◽  
pp. E8919-E8928 ◽  
Author(s):  
Govind Kunduri ◽  
Daniel Turner-Evans ◽  
Yutaka Konya ◽  
Yoshihiro Izumi ◽  
Kunio Nagashima ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Structure ◽  
Molecular Mechanisms ◽  
Visual Stimulation ◽  
Neuronal Cell ◽  
Sphingomyelin Synthase ◽  
Neuronal Cell Bodies ◽  
Evolutionarily Conserved ◽  
Photosensitive Epilepsy

Seizures induced by visual stimulation (photosensitive epilepsy; PSE) represent a common type of epilepsy in humans, but the molecular mechanisms and genetic drivers underlying PSE remain unknown, and no good genetic animal models have been identified as yet. Here, we show an animal model of PSE, in Drosophila, owing to defective cortex glia. The cortex glial membranes are severely compromised in ceramide phosphoethanolamine synthase (cpes)-null mutants and fail to encapsulate the neuronal cell bodies in the Drosophila neuronal cortex. Expression of human sphingomyelin synthase 1, which synthesizes the closely related ceramide phosphocholine (sphingomyelin), rescues the cortex glial abnormalities and PSE, underscoring the evolutionarily conserved role of these lipids in glial membranes. Further, we show the compromise in plasma membrane structure that underlies the glial cell membrane collapse in cpes mutants and leads to the PSE phenotype.

scholarly journals A multicellular rosette-mediated collective dendrite extension

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Li Fan ◽  
Ismar Kovacevic ◽  
Maxwell G Heiman ◽  
Zhirong Bao
Keyword(s):  
Adhesion Molecules ◽  
Molecular Mechanisms ◽  
Neural Circuits ◽  
Sensory Nerve ◽  
Neuronal Cell ◽  
Sensory Organ ◽  
Neurite Extension ◽  
C Elegans ◽  
Neuronal Cell Bodies

Coordination of neurite morphogenesis with surrounding tissues is crucial to the establishment of neural circuits, but the underlying cellular and molecular mechanisms remain poorly understood. We show that neurons in a C. elegans sensory organ, called the amphid, undergo a collective dendrite extension to form the sensory nerve. The amphid neurons first assemble into a multicellular rosette. The vertex of the rosette, which becomes the dendrite tips, is attached to the anteriorly migrating epidermis and carried to the sensory depression, extruding the dendrites away from the neuronal cell bodies. Multiple adhesion molecules including DYF-7, SAX-7, HMR-1 and DLG-1 function redundantly in rosette-to-epidermis attachment. PAR-6 is localized to the rosette vertex and dendrite tips, and promotes DYF-7 localization and dendrite extension. Our results suggest a collective mechanism of neurite extension that is distinct from the classical pioneer-follower model and highlight the role of mechanical cues from surrounding tissues in shaping neurites.

scholarly journals A multicellular rosette-mediated collective dendrite extension

2018 ◽  
Author(s):  
Li Fan ◽  
Ismar Kovacevic ◽  
Maxwell Heiman ◽  
Zhirong Bao
Keyword(s):  
Adhesion Molecules ◽  
Molecular Mechanisms ◽  
Neural Circuits ◽  
Sensory Nerve ◽  
Neuronal Cell ◽  
Sensory Organ ◽  
Neurite Extension ◽  
C Elegans ◽  
Neuronal Cell Bodies

Coordination of neurite morphogenesis with surrounding tissues is crucial to the establishment of neural circuits, but the underlying cellular and molecular mechanisms remain poorly understood. We show that neurons in a C. elegans sensory organ, called the amphid, undergo a collective dendrite extension to initiate formation of the sensory nerve. The amphid neurons first assemble into a multicellular rosette. The vertex of the rosette, which becomes the dendrite tips, is attached to the anteriorly migrating epidermis and carried to the sensory depression, extruding the dendrites away from the neuronal cell bodies. Multiple adhesion molecules including DYF-7, SAX-7, HMR-1 and DLG-1 function redundantly in rosette-to-epidermis attachment. PAR-6 is localized to the rosette vertex and dendrite tips, and promotes DYF-7 localization and dendrite extension. Our results suggest a collective mechanism of neurite extension that is distinct from the classical pioneer-follower model and highlight the role of mechanical cues from surrounding tissues in shaping neurites.

Role of vasopressin in sympathetic response to paraventricular nucleus stimulation in anesthetized rats

1994 ◽  
Vol 266 (1) ◽  
pp. R228-R236 ◽  
Author(s):  
S. C. Malpas ◽  
J. H. Coote
Keyword(s):  
Paraventricular Nucleus ◽  
Neuronal Cell ◽  
Detection Algorithm ◽  
Homocysteic Acid ◽  
Renal Sympathetic Nerve Activity ◽  
Anesthetized Rats ◽  
Neuronal Cell Bodies ◽  
Peak Detection Algorithm ◽  
Glass Micropipette

Vasopressin may play an extrahypothalamic role in the central control of the cardiovascular system, specifically acting as a spinal neurotransmitter in the pathway where the paraventricular nucleus (PVN) alters sympathetic outflow. In this study, the effect of stimulating neuronal cell bodies in the PVN on renal sympathetic nerve activity (RSNA) and the possible involvement of vasopressin in the pathway was investigated in anesthetized rats. The PVN was stimulated by microinjection with 0.2 M D,L-homocysteic acid via a glass micropipette, and the hemodynamic and sympathetic responses were recorded. A computerized sympathetic peak-detection algorithm was applied to recordings of sympathetic discharges to retrieve information about the characteristics of RSNA during PVN stimulation. The algorithm scanned the series of RSNA voltages for significant increases followed by significant decreases in a small cluster of voltage values. Once each synchronized RSNA peak had been detected, its corresponding amplitude and peak-to-peak interval were calculated. PVN stimulation consistently increased the amplitude of RSNA (mean 30 +/- 5.6% over control), arterial pressure, and the peak-to-peak interval of discharges. A V1 vasopressin antagonist intrathecally administered as a 500-pmol dose was subsequently able to completely block the hemodynamic response (blood pressure increase of 14 +/- 5%) and a 35 +/- 6% increase in RSNA in response to PVN stimulation and intrathecal vasopressin. Thus spinal vasopressin is likely to be a neurotransmitter involved in the cardiovascular regulation involving the PVN.

scholarly journals ESCRT-dependent targeting of plasma membrane localized KCa3.1 to the lysosomes

2010 ◽  
Vol 299 (5) ◽  
pp. C1015-C1027 ◽  
Author(s):  
Corina M. Balut ◽  
Yajuan Gao ◽  
Sandra A. Murray ◽  
Patrick H. Thibodeau ◽  
Daniel C. Devor
Keyword(s):  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Close Association ◽  
Significant Inhibition ◽  
Dominant Negative ◽  
Human Embryonic Kidney Cells ◽  
Endosomal Sorting ◽  
Escrt Machinery ◽  
Interfering Rna

The number of intermediate-conductance, Ca2+-activated K+ channels (KCa3.1) present at the plasma membrane is deterministic in any physiological response. However, the mechanisms by which KCa3.1 channels are removed from the plasma membrane and targeted for degradation are poorly understood. Recently, we demonstrated that KCa3.1 is rapidly internalized from the plasma membrane, having a short half-life in both human embryonic kidney cells (HEK293) and human microvascular endothelial cells (HMEC-1). In this study, we investigate the molecular mechanisms controlling the degradation of KCa3.1 heterologously expressed in HEK and HMEC-1 cells. Using immunofluorescence and electron microscopy, as well as quantitative biochemical analysis, we demonstrate that membrane KCa3.1 is targeted to the lysosomes for degradation. Furthermore, we demonstrate that either overexpressing a dominant negative Rab7 or short interfering RNA-mediated knockdown of Rab7 results in a significant inhibition of channel degradation rate. Coimmunoprecipitation confirmed a close association between Rab7 and KCa3.1. On the basis of these findings, we assessed the role of the ESCRT machinery in the degradation of heterologously expressed KCa3.1, including TSG101 [endosomal sorting complex required for transport (ESCRT)-I] and CHMP4 (ESCRT-III) as well as VPS4, a protein involved in the disassembly of the ESCRT machinery. We demonstrate that TSG101 is closely associated with KCa3.1 via coimmunoprecipitation and that a dominant negative TSG101 inhibits KCa3.1 degradation. In addition, both dominant negative CHMP4 and VPS4 significantly decrease the rate of membrane KCa3.1 degradation, compared with wild-type controls. These results are the first to demonstrate that plasma membrane-associated KCa3.1 is targeted for lysosomal degradation via a Rab7 and ESCRT-dependent pathway.

scholarly journals The role of FLOWERING LOCUS C in vernalization of Brassica: the importance of vernalization research in the face of climate change

2018 ◽  
Vol 69 (1) ◽  
pp. 30 ◽  
Author(s):  
Daniel J. Shea ◽  
Etsuko Itabashi ◽  
Satoko Takada ◽  
Eigo Fukai ◽  
Tomohiro Kakizaki ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Model Organism ◽  
Climatic Changes ◽  
Environmental Cues ◽  
Plant Responses ◽  
Agricultural Crops ◽  
Regulatory Pathways ◽  
Evolutionarily Conserved ◽  
The Face

As climatic changes occur over the coming decades, our scientific understanding of plant responses to environmental cues will become an increasingly important consideration in the breeding of agricultural crops. This review provides a summary of the literature regarding vernalization research in Brassicaceae, covering both the historical origins of vernalization research and current understanding of the molecular mechanisms behind the regulatory pathways involved in vernalization and subsequent inflorescence. We discuss the evolutionarily conserved biology between the model organism Arabidopsis thaliana and the Brassica genus of crop cultivars and contrast the differences between the genera to illustrate the importance of Brassica-specific research into vernalization.

Mechanism of protein sorting during erythroblast enucleation: role of cytoskeletal connectivity

Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1912-1919 ◽  
Author(s):  
James C.-M. Lee ◽  
J. Aura Gimm ◽  
Annie J. Lo ◽  
Mark J. Koury ◽  
Sharon W. Krauss ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Immunofluorescence Microscopy ◽  
Protein Sorting ◽  
Membrane Cytoskeleton ◽  
Skeletal Protein ◽  
Regulate Protein ◽  
Membrane Components ◽  
Cytoskeletal Elements

AbstractDuring erythroblast enucleation, nuclei surrounded by plasma membrane separate from erythroblast cytoplasm. A key aspect of this process is sorting of erythroblast plasma membrane components to reticulocytes and expelled nuclei. Although it is known that cytoskeletal elements actin and spectrin partition to reticulocytes, little is understood about molecular mechanisms governing plasma membrane protein sorting. We chose glycophorin A (GPA) as a model integral protein to begin investigating protein-sorting mechanisms. Using immunofluorescence microscopy and Western blotting we found that GPA sorted predominantly to reticulocytes. We hypothesized that the degree of skeletal linkage might control the sorting pattern of transmembrane proteins. To explore this hypothesis, we quantified the extent of GPA association to the cytoskeleton in erythroblasts, young reticulocytes, and mature erythrocytes using fluorescence imaged microdeformation (FIMD) and observed that GPA underwent dramatic reorganization during terminal differentiation. We discovered that GPA was more connected to the membrane cytoskeleton, either directly or indirectly, in erythroblasts and young reticulocytes than in mature cells. We conclude that skeletal protein association can regulate protein sorting during enucleation. Further, we suggest that the enhanced rigidity of reticulocyte membranes observed in earlier investigations results, at least in part, from increased connectivity of GPA with the spectrin-based skeleton.

scholarly journals Silencing of Plasma Membrane Ca2+-ATPase Isoforms 2 and 3 Impairs Energy Metabolism in Differentiating PC12 Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Tomasz Boczek ◽  
Malwina Lisek ◽  
Bozena Ferenc ◽  
Antoni Kowalski ◽  
Magdalena Wiktorska ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Pc12 Cells ◽  
Molecular Mechanisms ◽  
Atp Synthesis ◽  
Mitochondrial Activity ◽  
Excitable Cells ◽  
Close Link ◽  
Atp Level ◽  
Atp Generation

A close link between Ca2+, ATP level, and neurogenesis is apparent; however, the molecular mechanisms of this relationship have not been completely elucidated. Transient elevations of cytosolic Ca2+may boost ATP synthesis, but ATP is also consumed by ion pumps to maintain a low Ca2+in cytosol. In differentiation process plasma membrane Ca2+ATPase (PMCA) is considered as one of the major players for Ca2+homeostasis. From four PMCA isoforms, the fastest PMCA2 and PMCA3 are expressed predominantly in excitable cells. In the present study we assessed whether PMCA isoform composition may affect energy balance in differentiating PC12 cells. We found that PMCA2-downregulated cells showed higher basal O2consumption, lower NAD(P)H level, and increased activity of ETC. These changes associated with higher[Ca2+]cresulted in elevated ATP level. Since PMCA2-reduced cells demonstrated greatest sensitivity to ETC inhibition, we suppose that the main source of energy for PMCA isoforms 1, 3, and 4 was oxidative phosphorylation. Contrary, cells with unchanged PMCA2 expression exhibited prevalence of glycolysis in ATP generation. Our results with PMCA2- or PMCA3-downregulated lines provide an evidence of a novel role of PMCA isoforms in regulation of bioenergetic pathways, and mitochondrial activity and maintenance of ATP level during PC12 cells differentiation.

scholarly journals Cytoplasmic Cl− couples membrane remodeling to epithelial morphogenesis

2017 ◽  
Vol 114 (52) ◽  
pp. E11161-E11169 ◽  
Author(s):  
Mu He ◽  
Wenlei Ye ◽  
Won-Jing Wang ◽  
Eirish S. Sison ◽  
Yuh Nung Jan ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Adherens Junction ◽  
Epithelial Morphogenesis ◽  
Membrane Remodeling ◽  
Organelle Biogenesis ◽  
Critical Function ◽  
Animal Development ◽  
Evolutionarily Conserved ◽  
Water Secretion

Chloride is the major free anion in the extracellular space (>100 mM) and within the cytoplasm in eukaryotes (10 ∼ 20 mM). Cytoplasmic Cl− level is dynamically regulated by Cl− channels and transporters. It is well established that movement of Cl− across the cell membrane is coupled with cell excitability through changes in membrane potential and with water secretion. However, whether cytoplasmic Cl− plays additional roles in animal development and tissue homeostasis is unknown. Here we use genetics, cell biological and pharmacological tools to demonstrate that TMEM16A, an evolutionarily conserved calcium-activated chloride channel (CaCC), regulates cytoplasmic Cl− homeostasis and promotes plasma membrane remodeling required for mammalian epithelial morphogenesis. We demonstrate that TMEM16A-mediated control of cytoplasmic Cl− regulates the organization of the major phosphoinositide species PtdIns(4,5)P2 into microdomains on the plasma membrane, analogous to processes that cluster soluble and membrane proteins into phase-separated droplets. We further show that an adequate cytoplasmic Cl− level is required for proper endocytic trafficking and membrane supply during early stages of ciliogenesis and adherens junction remodeling. Our study thus uncovers a critical function of CaCC-mediated cytoplasmic Cl− homeostasis in controlling the organization of PtdIns(4,5)P2 microdomains and membrane remodeling. This newly defined role of cytoplasmic Cl− may shed light on the mechanisms of intracellular Cl− signaling events crucial for regulating tissue architecture and organelle biogenesis during animal development.

scholarly journals The central role of mitochondria in axonal degeneration in multiple sclerosis

2014 ◽  
Vol 20 (14) ◽  
pp. 1806-1813 ◽  
Author(s):  
Graham R Campbell ◽  
Joseph T Worrall ◽  
Don J Mahad
Keyword(s):  
Multiple Sclerosis ◽  
Axonal Degeneration ◽  
Neuronal Cell ◽  
Mitochondrial Respiratory Chain ◽  
Respiratory Chain Complexes ◽  
Autoimmune Encephalomyelitis ◽  
Mitochondrial Abnormalities ◽  
Neuronal Cell Bodies ◽  
Chain Complexes

Neurodegeneration in multiple sclerosis (MS) is related to inflammation and demyelination. In acute MS lesions and experimental autoimmune encephalomyelitis focal immune attacks damage axons by injuring axonal mitochondria. In progressive MS, however, axonal damage occurs in chronically demyelinated regions, myelinated regions and also at the active edge of slowly expanding chronic lesions. How axonal energy failure occurs in progressive MS is incompletely understood. Recent studies show that oligodendrocytes supply lactate to myelinated axons as a metabolic substrate for mitochondria to generate ATP, a process which will be altered upon demyelination. In addition, a number of studies have identified mitochondrial abnormalities within neuronal cell bodies in progressive MS, leading to a deficiency of mitochondrial respiratory chain complexes or enzymes. Here, we summarise the mitochondrial abnormalities evident within neurons and discuss how these grey matter mitochondrial abnormalities may increase the vulnerability of axons to degeneration in progressive MS. Although neuronal mitochondrial abnormalities will culminate in axonal degeneration, understanding the different contributions of mitochondria to the degeneration of myelinated and demyelinated axons is an important step towards identifying potential therapeutic targets for progressive MS.

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