scholarly journals Circulating Hedgehog: a fresh view of a classic morphogen

Development ◽  
2020 ◽  
Vol 147 (24) ◽  
pp. dev186395 ◽  
Author(s):  
Elodie Prince ◽  
Julien Marcetteau ◽  
Pascal P. Thérond
Keyword(s):  
Intercellular Communication ◽  
Extracellular Space ◽  
Animal Tissues ◽  
Lipoprotein Particles ◽  
Seminal Work ◽  
Endocrine Hormone ◽  
Shed Light

ABSTRACTMembers of the Hedgehog family of morphogens mediate the intercellular communication necessary for the organisation and development of many animal tissues. They are modified by various lipid adducts, rendering them insoluble in hydrophilic environments and leading to the contentious question of how these molecules travel in the aqueous extracellular space. Seminal work carried out by Suzanne Eaton and her colleagues has shed light on how these morphogens can spread over long distances through their association with lipoprotein particles. In this Spotlight article, we discuss Suzanne's pioneering work and her contribution to our understanding of the transport and activity of morphogens, in particular Hedgehog. We also describe two other essential aspects of her work: the discovery and characterisation of endogenously present Hedgehog variants, as well as her proposition that, in addition to its role as a morphogen, Hedgehog acts as an endocrine hormone.

scholarly journals Perfusion Fixation of Research Animals

2006 ◽  
Vol 14 (3) ◽  
pp. 26-33 ◽  
Author(s):  
Charles W. Scouten ◽  
Ryan O'Connor ◽  
Miles Cunningham
Keyword(s):  
Brain Tissue ◽  
Extracellular Space ◽  
Soft Tissues ◽  
Brain Size ◽  
Animal Tissues ◽  
Tissue Samples ◽  
Vascular Channel ◽  
Organ Volume ◽  
Perfusion Fixation

Perfusion, washing out blood and using the open vascular channel to infuse fixative, is the standard first step of preparing animal tissues for later examination under a microscope. The rapid and homogeneous fixation resulting provides an advantage over immersion fixation that is usually used for biopsy and clinical tissue samples (Cammermeyer, 1960, Garman, 1990). A disadvantage is that brain tissue, and probably other soft tissues, prepared by perfusion has no retained extracellular space post perfusion, although living brain has about 20% extracellular space (discussed in Cragg, 1980). Perfused brain is also about 20% shrunk in whole organ volume from living brain size. The shrinkage is uneven, and distorts the relationships of structures. It is possible to avoid the organ shrinkage and distortion that follows a traditional perfusion, with little additional effort. This is a discussion of how to optimize your perfusion results, why the shrinkage occurs, and how it can be avoided.

scholarly journals Opposing functions for retromer and Rab11 in extracellular vesicle traffic at presynaptic terminals

2021 ◽  
Vol 220 (8) ◽  
Author(s):  
Rylie B. Walsh ◽  
Erica C. Dresselhaus ◽  
Agata N. Becalska ◽  
Matthew J. Zunitch ◽  
Cassandra R. Blanchette ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Intercellular Communication ◽  
Neurological Disease ◽  
Extracellular Vesicle ◽  
Membrane Recycling ◽  
Presynaptic Terminals ◽  
Vesicle Traffic ◽  
Retromer Complex ◽  
Shed Light ◽  
Competing Pathways

Neuronal extracellular vesicles (EVs) play important roles in intercellular communication and pathogenic protein propagation in neurological disease. However, it remains unclear how cargoes are selectively packaged into neuronal EVs. Here, we show that loss of the endosomal retromer complex leads to accumulation of EV cargoes including amyloid precursor protein (APP), synaptotagmin-4 (Syt4), and neuroglian (Nrg) at Drosophila motor neuron presynaptic terminals, resulting in increased release of these cargoes in EVs. By systematically exploring known retromer-dependent trafficking mechanisms, we show that EV regulation is separable from several previously identified roles of neuronal retromer. Conversely, mutations in rab11 and rab4, regulators of endosome-plasma membrane recycling, cause reduced EV cargo levels, and rab11 suppresses cargo accumulation in retromer mutants. Thus, EV traffic reflects a balance between Rab4/Rab11 recycling and retromer-dependent removal from EV precursor compartments. Our data shed light on previous studies implicating Rab11 and retromer in competing pathways in Alzheimer’s disease, and suggest that misregulated EV traffic may be an underlying defect.

scholarly journals On the role of the extracellular space on the holistic behavior of the brain

2015 ◽  
Vol 26 (5) ◽  
pp. 489-506 ◽  
Author(s):  
Manuela Marcoli ◽  
Luigi F. Agnati ◽  
Francesco Benedetti ◽  
Susanna Genedani ◽  
Diego Guidolin ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Extracellular Matrix ◽  
Nervous System ◽  
Cellular Networks ◽  
Intercellular Communication ◽  
Extracellular Space ◽  
Cell Types ◽  
Molecular Network ◽  
The Central Nervous System ◽  
The Brain

AbstractMultiple players are involved in the brain integrative action besides the classical neuronal and astrocyte networks. In the past, the concept of complex cellular networks has been introduced to indicate that all the cell types in the brain can play roles in its integrative action. Intercellular communication in the complex cellular networks depends not only on well-delimited communication channels (wiring transmission) but also on diffusion of signals in physically poorly delimited extracellular space pathways (volume transmission). Thus, the extracellular space and the extracellular matrix are the main players in the intercellular communication modes in the brain. Hence, the extracellular matrix is an ‘intelligent glue’ that fills the brain and, together with the extracellular space, contributes to the building-up of the complex cellular networks. In addition, the extracellular matrix is part of what has been defined as the global molecular network enmeshing the entire central nervous system, and plays important roles in synaptic contact homeostasis and plasticity. From these premises, a concept is introduced that the global molecular network, by enmeshing the central nervous system, contributes to the brain holistic behavior. Furthermore, it is suggested that plastic ‘brain compartments’ can be detected in the central nervous system based on the astrocyte three-dimensional tiling of the brain volume and on the existence of local differences in cell types and extracellular space fluid and extracellular matrix composition. The relevance of the present view for neuropsychiatry is discussed. A glossary box with terms and definitions is provided.

Neurotransmitters and Neurohormones

The Neuron ◽  
2015 ◽  
pp. 213-238
Author(s):  
Irwin B. Levitan ◽  
Leonard K. Kaczmarek
Keyword(s):  
Nervous System ◽  
Glial Cells ◽  
Target Cell ◽  
Calcium Ions ◽  
Intercellular Communication ◽  
Extracellular Space ◽  
Presynaptic Terminal ◽  
Nerve Terminals ◽  
Transporter Proteins

A multitude of chemicals called neurotransmitters mediate intercellular communication in the nervous system. These include acetylcholine, the catecholamines, serotonin, glutamate, GABA, glycine, and a wide variety of neuropeptides. Although they exhibit great diversity in many of their properties, all are stored in vesicles in nerve terminals and are released to the extracellular space via a process requiring calcium ions. Their actions are terminated by reuptake into the presynaptic terminal or nearby glial cells by specific transporter proteins or by their destruction in the extracellular space. The role of neurotransmitters is to alter the properties—chemical, electrical, or both—of some target cell. With the arrival on the scene of the neuropeptides, it has become evident that signaling in the nervous system occurs through the use of rich and varied forms of chemical currency, and that some neurons use more than one type of currency simultaneously.

Hinges, Prejudices, and Radical Doubters

2019 ◽  
Vol 10 (1) ◽  
pp. 165-181
Author(s):  
Anna Boncompagni
Keyword(s):  
Reasonable Doubt ◽  
Epistemic Injustice ◽  
Social Transformations ◽  
Epistemic Practices ◽  
Seminal Work ◽  
Hinge Epistemology ◽  
Shed Light

AbstractThis paper makes use of the Wittgenstein-inspired perspective of hinge epistemology in connection with research on epistemic injustice. Its aim is to shed light on the neglected relationship between hinges and prejudices, by focussing on the role of the “radical doubter” in epistemic practices. After the introduction, section 1 presents Miranda Fricker’s (2007) seminal work and points out that epistemic injustice typically involves the silence of discriminated groups, an aspect that emerges with most clarity when the figure of the doubter is considered. This is further investigated in section 2 with the examination of the film “Twelve Angry Men”, by Sidney Lumet. Some unsolved problems posed by Lumet’s film, rotating around the notion of reasonable doubt, are addressed in the following section through the Wittgensteinian metaphor of hinges as developed in hinge epistemology. Finally, by bringing together epistemic injustice and hinge epistemology, section 4 puts to the fore the importance of cultivating the capacity of attention towards radical doubters for understanding one’s own prejudices and promoting social transformations.

scholarly journals Opposing functions for retromer and Rab11 in extracellular vesicle cargo traffic at presynaptic terminals

2019 ◽  
Author(s):  
Rylie B. Walsh ◽  
Agata N. Becalska ◽  
Matthew J. Zunitch ◽  
Tania Lemos ◽  
Erica C. Dresselhaus ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Motor Neuron ◽  
Intercellular Communication ◽  
Neurological Disease ◽  
Extracellular Vesicle ◽  
Presynaptic Terminals ◽  
Recycling Endosome ◽  
Retromer Complex ◽  
Shed Light ◽  
Competing Pathways

ABSTRACTNeuronal extracellular vesicles (EVs) play important roles in intercellular communication and pathogenic protein propagation in neurological disease. However, it remains unclear how cargoes are selectively packaged into neuronal EVs. Here, we show that loss of the endosomal retromer complex leads to accumulation of EV cargoes Amyloid Precursor Protein (APP) and Synaptotagmin-4 (Syt4) at Drosophila motor neuron presynaptic terminals, resulting in increased release of these cargoes in EVs. By systematically exploring known retromer-dependent trafficking mechanisms, we show that EV regulation is separable from several previously identified roles of neuronal retromer, and depends on the ESCPE-1 complex. Conversely, loss of the recycling endosome regulator rab11 leads to reduced EV cargo levels, and suppresses cargo accumulation in retromer mutants. Thus, EV traffic reflects a balance between Rab11-mediated loading and retromer-dependent removal from EV precursor compartments. Our data shed light on previous studies implicating Rab11 and retromer in competing pathways in Alzheimer’s Disease, and suggest that misregulated EV traffic may be an underlying defect.

Exosomes as mediators and biomarkers in fibrosis

2020 ◽  
Vol 14 (8) ◽  
pp. 697-712 ◽  
Author(s):  
Xi-ji Qin ◽  
Jia-xiang Zhang ◽  
Rui-lan Wang
Keyword(s):  
Extracellular Matrix ◽  
Organ Failure ◽  
Intercellular Communication ◽  
Extracellular Space ◽  
Therapeutic Targets ◽  
Special Focus ◽  
Matrix Deposition ◽  
Therapeutic Value ◽  
Extracellular Matrix Deposition ◽  
Fibrotic Diseases

Fibrosis is characterized by aberrant myofibroblast accumulation and excessive extracellular matrix deposition, which leads to organ failure and significantly contributes to mortality worldwide. Exosomes, which are extracellular nanovesicles with a diameter of 30–100 nm that are secreted into the extracellular space by various types of cells, facilitate intercellular communication by delivering different cargos such as proteins, mRNAs and microRNAs. Growing evidence indicates that exosomes play an important role in various fibrotic diseases. A deeper understanding of the effects of exosomes in fibrosis may help in exploring new diagnostic and therapeutic targets. In this review, we summarize recent findings on exosomes in fibrotic diseases, with a special focus on exosomal cargo dysregulation and their potential diagnostic and therapeutic value in fibrosis.

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