scholarly journals Dystroglycan is a scaffold for extracellular axon guidance decisions

2018 ◽  
Author(s):  
L. Bailey Lindenmaier ◽  
Nicolas Parmentier ◽  
Caying Guo ◽  
Fadel Tissir ◽  
Kevin M Wright
Keyword(s):  
Axon Guidance ◽  
Matrix Proteins ◽  
Environmental Cues ◽  
Transmembrane Receptors ◽  
Binding Partner ◽  
Transmembrane Glycoprotein ◽  
Extracellular Signaling ◽  
Brain And Spinal Cord ◽  
The Brain

SummaryAxon guidance requires interactions between extracellular signaling molecules and transmembrane receptors, but how appropriate context-dependent decisions are coordinated outside the cell remains unclear. Here we show that the transmembrane glycoprotein Dystroglycan interacts with a changing set of environmental cues that regulate the trajectories of extending axons throughout the brain and spinal cord. Dystroglycan operates primarily as an extracellular scaffold during axon guidance, as it functions non-cell autonomously and does not require signaling through its intracellular domain. We identify the transmembrane receptor Celsr3/Adgrc3 as a binding partner for Dystroglycan, and show that this interaction is critical for specific axon guidance events in vivo. These findings establish Dystroglycan as a multifunctional scaffold that coordinates extracellular matrix proteins, secreted cues, and transmembrane receptors to regulate axon guidance.

scholarly journals Dystroglycan is a scaffold for extracellular axon guidance decisions

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
L Bailey Lindenmaier ◽  
Nicolas Parmentier ◽  
Caiying Guo ◽  
Fadel Tissir ◽  
Kevin M Wright
Keyword(s):  
Axon Guidance ◽  
Matrix Proteins ◽  
Mammalian Brain ◽  
Environmental Cues ◽  
Transmembrane Receptors ◽  
Binding Partner ◽  
Transmembrane Glycoprotein ◽  
Extracellular Signaling ◽  
Brain And Spinal Cord

Axon guidance requires interactions between extracellular signaling molecules and transmembrane receptors, but how appropriate context-dependent decisions are coordinated outside the cell remains unclear. Here we show that the transmembrane glycoprotein Dystroglycan interacts with a changing set of environmental cues that regulate the trajectories of extending axons throughout the mammalian brain and spinal cord. Dystroglycan operates primarily as an extracellular scaffold during axon guidance, as it functions non-cell autonomously and does not require signaling through its intracellular domain. We identify the transmembrane receptor Celsr3/Adgrc3 as a binding partner for Dystroglycan, and show that this interaction is critical for specific axon guidance events in vivo. These findings establish Dystroglycan as a multifunctional scaffold that coordinates extracellular matrix proteins, secreted cues, and transmembrane receptors to regulate axon guidance.

scholarly journals Recapitulate development to promote axonal regeneration: good or bad approach?

2006 ◽  
Vol 361 (1473) ◽  
pp. 1565-1574 ◽  
Author(s):  
Marie T Filbin
Keyword(s):  
Spinal Cord ◽  
Axonal Regeneration ◽  
Molecular Level ◽  
Signal Transduction Pathway ◽  
Developmental Changes ◽  
Transduction Pathway ◽  
The Past ◽  
Brain And Spinal Cord ◽  
The Brain

In the past decade there has been an explosion in our understanding, at the molecular level, of why axons in the adult, mammalian central nervous system (CNS) do not spontaneously regenerate while their younger counterparts do. Now a number of inhibitors of axonal regeneration have been described, some of the receptors they interact with to transduce the inhibitory signal are known, as are some of the steps in the signal transduction pathway that is responsible for inhibition. In addition, developmental changes in the environment and in the neurons themselves are also now better understood. This knowledge in turn reveals novel, putative sites for drug development and therapeutic intervention after injury to the brain and spinal cord. The challenge now is to determine which of these putative treatments are the most effective and if they would be better applied in combination rather than alone. In this review I will summarize what we have learnt about these molecules and how they signal. Importantly, I will also describe approches that have been shown to block inhibitors and encourage regeneration in vivo . I will also speculate on what the differences are between the neonatal and adult CNS that allow the former to regenerate and the latter not to.

Imaging

2017 ◽  
Author(s):  
Robert Laureno
Keyword(s):  
Resonance Imaging ◽  
Cross Sectional ◽  
Advantages And Disadvantages ◽  
Mri Scans ◽  
Cross Sectional Imaging ◽  
Magnetic Resonance Imaging Mri ◽  
Cellular Pathology ◽  
Brain And Spinal Cord ◽  
The Brain

This chapter on “Imaging” examines the relative advantages and disadvantages of computed tomography (CT) and magnetic resonance imaging (MRI) scans. It compares the modalities to each other and to gross neuropathology. For several decades, neurologists have been able to view cross-sectional images of living patients. Analogous to gross neuropathology, cross-sectional imaging displays the brain as an entire organ but does not demonstrate microscopic tissue or cellular pathology. By allowing practitioners to view sections of brain and spinal cord in vivo, imaging has improved neurologic practice and facilitated clinical research. This chapter deals with imaging topics that are important to the neurologist. The timing of scans, the effects of gravity, and the importance of plane of section are considered. Imaging is compared to gross neuropathology, and MRI is compared to CT.

scholarly journals The vascular basement membrane in the healthy and pathological brain

2017 ◽  
Vol 37 (10) ◽  
pp. 3300-3317 ◽  
Author(s):  
Maj S Thomsen ◽  
Lisa J Routhe ◽  
Torben Moos
Keyword(s):  
Drug Delivery ◽  
Basement Membrane ◽  
Proteolytic Enzymes ◽  
Three Dimensional ◽  
Matrix Proteins ◽  
Vascular Basement Membrane ◽  
Capillary Endothelial Cells ◽  
The Brain ◽  
Astrocyte Endfeet

The vascular basement membrane contributes to the integrity of the blood-brain barrier (BBB), which is formed by brain capillary endothelial cells (BCECs). The BCECs receive support from pericytes embedded in the vascular basement membrane and from astrocyte endfeet. The vascular basement membrane forms a three-dimensional protein network predominantly composed of laminin, collagen IV, nidogen, and heparan sulfate proteoglycans that mutually support interactions between BCECs, pericytes, and astrocytes. Major changes in the molecular composition of the vascular basement membrane are observed in acute and chronic neuropathological settings. In the present review, we cover the significance of the vascular basement membrane in the healthy and pathological brain. In stroke, loss of BBB integrity is accompanied by upregulation of proteolytic enzymes and degradation of vascular basement membrane proteins. There is yet no causal relationship between expression or activity of matrix proteases and the degradation of vascular matrix proteins in vivo. In Alzheimer’s disease, changes in the vascular basement membrane include accumulation of Aβ, composite changes, and thickening. The physical properties of the vascular basement membrane carry the potential of obstructing drug delivery to the brain, e.g. thickening of the basement membrane can affect drug delivery to the brain, especially the delivery of nanoparticles.

scholarly journals Effects of Red Ginseng on Neural Injuries with Reference to the Molecular Mechanisms

J ◽  
2019 ◽  
Vol 2 (2) ◽  
pp. 116-127
Author(s):  
Pengxiang Zhu ◽  
Masahiro Sakanaka
Keyword(s):  
Molecular Mechanisms ◽  
Bioactive Molecules ◽  
Red Ginseng ◽  
Promising Candidate ◽  
Neuroprotective Effects ◽  
Chemical Structures ◽  
Brain And Spinal Cord ◽  
The Brain

Red ginseng, as an effective herbal medicine, has been traditionally and empirically used for the treatment of neuronal diseases. Many studies suggest that red ginseng and its ingredients protect the brain and spinal cord from neural injuries such as ischemia, trauma, and neurodegeneration. This review focuses on the molecular mechanisms underlying the neuroprotective effects of red ginseng and its ingredients. Ginsenoside Rb1 and other ginsenosides are regarded as the active ingredients of red ginseng; the anti-apoptotic, anti-inflammatory, and anti-oxidative actions of ginsenosides, together with a series of bioactive molecules relevant to the above actions, appear to account for the neuroprotective effects in vivo and/or in vitro. Moreover, in this review, the possibility is raised that more effective or stable neuroprotective derivatives based on the chemical structures of ginsenosides could be developed. Although further studies, including clinical trials, are necessary to confirm the pharmacological properties of red ginseng and its ingredients, red ginseng and its ingredients could be promising candidate drugs for the treatment of neural injuries.

scholarly journals Frazzled promotes growth cone attachment at the source of a Netrin gradient in the Drosophila visual system

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Orkun Akin ◽  
S Lawrence Zipursky
Keyword(s):  
Colorectal Cancer ◽  
Visual System ◽  
Axon Guidance ◽  
Growth Cone ◽  
Short Range ◽  
Growth Cones ◽  
Live Imaging ◽  
Deleted In Colorectal Cancer ◽  
Binding Partner

Axon guidance is proposed to act through a combination of long- and short-range attractive and repulsive cues. The ligand-receptor pair, Netrin (Net) and Frazzled (Fra) (DCC, Deleted in Colorectal Cancer, in vertebrates), is recognized as the prototypical effector of chemoattraction, with roles in both long- and short-range guidance. In the Drosophila visual system, R8 photoreceptor growth cones were shown to require Net-Fra to reach their target, the peak of a Net gradient. Using live imaging, we show, however, that R8 growth cones reach and recognize their target without Net, Fra, or Trim9, a conserved binding partner of Fra, but do not remain attached to it. Thus, despite the graded ligand distribution along the guidance path, Net-Fra is not used for chemoattraction. Based on findings in other systems, we propose that adhesion to substrate-bound Net underlies both long- and short-range Net-Fra-dependent guidance in vivo, thereby eroding the distinction between them.

scholarly journals The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

2020 ◽  
Author(s):  
Tracy J. Berg ◽  
Carolina Marques ◽  
Vasiliki Pantazopoulou ◽  
Elinn Johansson ◽  
Kristoffer von Stedingk ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Glioma Cells ◽  
Transglutaminase 2 ◽  
Standard Of Care ◽  
Matrix Proteins ◽  
Human Glioma ◽  
Radiation Induced ◽  
Aggressive Tumors ◽  
The Brain

AbstractThe tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance, and following radiotherapy, recurrent gliomas form in an irradiated microenvironment. Here, we found that astrocytes, when pre-irradiated, increased stemness and survival of co-cultured glioma cells. Tumor-naïve brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. We identified extracellular matrix derived from irradiated astrocytes as a major driver of this phenotype, and astrocyte-derived transglutaminase 2 (TGM2) as a promoter of glioma stemness and radioresistance. TGM2 levels were increased after radiation in vivo and in recurrent human glioma, and TGM2 inhibitors abrogated glioma stemness and survival. These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard of care radiotherapy by reducing stemness in glioma.

scholarly journals Autophagy linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Joanna M Dragich ◽  
Takaaki Kuwajima ◽  
Megumi Hirose-Ikeda ◽  
Michael S Yoon ◽  
Evelien Eenjes ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Axon Guidance ◽  
Mouse Genetics ◽  
Mammalian Brain ◽  
Complex Cell ◽  
Neuronal Connectivity ◽  
Molecular Scaffold ◽  
Evolutionarily Conserved ◽  
Brain And Spinal Cord ◽  
The Brain

The regulation of protein degradation is essential for maintaining the appropriate environment to coordinate complex cell signaling events and to promote cellular remodeling. The Autophagy linked FYVE protein (Alfy), previously identified as a molecular scaffold between the ubiquitinated cargo and the autophagic machinery, is highly expressed in the developing central nervous system, indicating that this pathway may have yet unexplored roles in neurodevelopment. To examine this possibility, we used mouse genetics to eliminate Alfy expression. We report that this evolutionarily conserved protein is required for the formation of axonal tracts throughout the brain and spinal cord, including the formation of the major forebrain commissures. Consistent with a phenotype reflecting a failure in axon guidance, the loss of Alfy in mice disrupts localization of glial guidepost cells, and attenuates axon outgrowth in response to Netrin-1. These findings further support the growing indication that macroautophagy plays a key role in the developing CNS.

scholarly journals MRI- and histologically derived neuroanatomical atlas of the Ambystoma mexicanum (axolotl)

2020 ◽  
Author(s):  
Iván Lazcano ◽  
Abraham Cisneros-Mejorado ◽  
Luis Concha ◽  
Juan José Ortíz Retana ◽  
Eduardo A. Garza-Villarreal ◽  
...  
Keyword(s):  
Ambystoma Mexicanum ◽  
Brain Atlas ◽  
Future Research ◽  
Brain Anatomy ◽  
Vertebrate Model ◽  
Left And Right ◽  
Brain And Spinal Cord ◽  
The Brain ◽  
Recent Sequencing

AbstractAmphibians are an important vertebrate model system to understand anatomy, genetics and physiology. Importantly, the brain and spinal cord of adult urodels (salamanders) have an incredible regeneration capacity, contrary to anurans (frogs) and the rest of adult vertebrates. Among these amphibians, the axolotl (Ambystoma mexicanum) has gained most attention because of the surge in the understanding of CNS regeneration and the recent sequencing of its whole genome. However, a complete comprehension of the brain anatomy is not available. In the present study we created a magnetic resonance imaging atlas of the in vivo neuroanatomy of the juvenile axolotl brain. This is the first MRI atlas for this species and includes 3 levels: 1) 80 regions of interest (ROIs); 2) a division of the brain according to the embryological origin of the neural tube, and 3) left and right hemispheres. Additionally, we localized the myelin rich regions of the juvenile brain. The atlas, the template that the atlas was derived from, and a masking file, can be found on Zenodo at DOI: 10.5281/zenodo.4311937. This MRI brain atlas aims to be an important tool for future research of the axolotl brain and that of other amphibians.

scholarly journals Applications of CRISPR-Cas9 Technology to Genome Editing in Glioblastoma Multiforme

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2342
Author(s):  
Nadia Al-Sammarraie ◽  
Swapan K. Ray
Keyword(s):  
Glioblastoma Multiforme ◽  
Genome Editing ◽  
Gene Editing ◽  
Current Knowledge ◽  
Cost Effective ◽  
Genetic Alterations ◽  
Brain And Spinal Cord ◽  
The Brain

Glioblastoma multiforme (GBM) is an aggressive malignancy of the brain and spinal cord with a poor life expectancy. The low survivability of GBM patients can be attributed, in part, to its heterogeneity and the presence of multiple genetic alterations causing rapid tumor growth and resistance to conventional therapy. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR associated (Cas) nuclease 9 (CRISPR-Cas9) system is a cost-effective and reliable gene editing technology, which is widely used in cancer research. It leads to novel discoveries of various oncogenes that regulate autophagy, angiogenesis, and invasion and play important role in pathogenesis of various malignancies, including GBM. In this review article, we first describe the principle and methods of delivery of CRISPR-Cas9 genome editing. Second, we summarize the current knowledge and major applications of CRISPR-Cas9 to identifying and modifying the genetic regulators of the hallmark of GBM. Lastly, we elucidate the major limitations of current CRISPR-Cas9 technology in the GBM field and the future perspectives. CRISPR-Cas9 genome editing aids in identifying novel coding and non-coding transcriptional regulators of the hallmarks of GBM particularly in vitro, while work using in vivo systems requires further investigation.

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