Pioneer Midbrain Longitudinal Axons Navigate Using a Balance of Netrin Attraction and Slit Repulsion Kim Et Al
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Neurexin Ilia: Extensive Alternative Splicing Generates Membrane-Bound and Soluble Forms Yuri A
Proc. Natl. Acad. Sci. USA Vol. 90, pp. 6410-6414, July 1993 Biochemistry Neurexin IlIa: Extensive alternative splicing generates membrane-bound and soluble forms YURi A. USHKARYOV AND THOMAS C. SUDHOF* Howard Hughes Medical Institute and Department of Molecular Genetics, University of Texas Southwestern Medical School, Dallas, TX 75235 Communicated by Michael S. Brown, March 26, 1993 ABSTRACT The structure ofneurexin lIa was elucidated and 13-neurexins have identical C termini including the from overlapping cDNA clones. Neurexin lIa is highly ho- 0-linked sugar region, transmembrane region, and cytoplas- mologous to neurexins la and Ha and shares with them a mic domain (2). distinctive domain structure that resembles a cell surface Structures of the neurexins are suggestive of cell surface receptor. cDNA cloning and PCR experiments revealed alter- receptors. Indeed, the neurexins were originally found be- native splicing at four positions in the mRNA for neurexin HIa. cause of the identity of the sequence of neurexin Ia and Alternative splicing was previously observed at the same po- sequences from the high molecular weight subunit of the sitions in either neurexin Ia or neurexin Ila or both, suggesting receptor for a presynaptic neurotoxin, a-latrotoxin (7). Im- that the three neurexins are subject to extensive alternative munocytochemistry ofrat brain frozen sections revealed that splicing. This results in hundreds of different neurexins with neurexin I is highly enriched in synapses in agreement with variations in small sequences at similar positions in the pro- the localization of a-latrotoxin (2). These findings suggest teins. The most extensive alternative splicing of neurexin Ma that at least neurexins Ia and I13 are synaptic proteins that, was detected at its C-terminal site, which exhibits a minimum based on their structure and homologies, may represent a of 12 variants. -
Understanding Axon Guidance: Are We Nearly There Yet?
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2018 Understanding axon guidance: are we nearly there yet? Stoeckli, Esther T Abstract: During nervous system development, neurons extend axons to reach their targets and form functional circuits. The faulty assembly or disintegration of such circuits results in disorders of the nervous system. Thus, understanding the molecular mechanisms that guide axons and lead to neural circuit formation is of interest not only to developmental neuroscientists but also for a better comprehension of neural disorders. Recent studies have demonstrated how crosstalk between different families of guidance receptors can regulate axonal navigation at choice points, and how changes in growth cone behaviour at intermediate targets require changes in the surface expression of receptors. These changes can be achieved by a variety of mechanisms, including transcription, translation, protein-protein interactions, and the specific trafficking of proteins and mRNAs. Here, I review these axon guidance mechanisms, highlighting the most recent advances in the field that challenge the textbook model of axon guidance. DOI: https://doi.org/10.1242/dev.151415 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-166034 Journal Article Published Version Originally published at: Stoeckli, Esther T (2018). Understanding axon guidance: are we nearly there yet? Development, 145(10):dev151415. DOI: https://doi.org/10.1242/dev.151415 © 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev151415. doi:10.1242/dev.151415 REVIEW Understanding axon guidance: are we nearly there yet? Esther T. -
Lysosomal Function and Axon Guidance: Is There a Meaningful Liaison?
biomolecules Review Lysosomal Function and Axon Guidance: Is There a Meaningful Liaison? Rosa Manzoli 1,2,†, Lorenzo Badenetti 1,3,4,†, Michela Rubin 1 and Enrico Moro 1,* 1 Department of Molecular Medicine, University of Padova, 35121 Padova, Italy; [email protected] (R.M.); [email protected] (L.B.); [email protected] (M.R.) 2 Department of Biology, University of Padova, 35121 Padova, Italy 3 Department of Women’s and Children’s Health, University of Padova, 35121 Padova, Italy 4 Pediatric Research Institute “Città della Speranza”, 35127 Padova, Italy * Correspondence: [email protected]; Tel.: +39-04-98276341 † These authors contributed equally to this paper. Abstract: Axonal trajectories and neural circuit activities strongly rely on a complex system of molec- ular cues that finely orchestrate the patterning of neural commissures. Several of these axon guidance molecules undergo continuous recycling during brain development, according to incompletely un- derstood intracellular mechanisms, that in part rely on endocytic and autophagic cascades. Based on their pivotal role in both pathways, lysosomes are emerging as a key hub in the sophisticated regulation of axonal guidance cue delivery, localization, and function. In this review, we will attempt to collect some of the most relevant research on the tight connection between lysosomal function and axon guidance regulation, providing some proof of concepts that may be helpful to understanding the relation between lysosomal storage disorders and neurodegenerative diseases. Citation: Manzoli, R.; Badenetti, L.; Keywords: axon guidance; lysosomal storage disorders; neuronal circuit Rubin, M.; Moro, E. Lysosomal Function and Axon Guidance: Is There a Meaningful Liaison? Biomolecules 2021, 11, 191. -
Discovery of a Functional Protein Complex of Netrin-4, Laminin 1 Chain
Discovery of a functional protein complex of netrin-4, laminin ␥1 chain, and integrin ␣61 in mouse neural stem cells Fernanda I. Staquicinia, Emmanuel Dias-Netoa, Jianxue Lib, Evan Y. Snyderc,d,e, Richard L. Sidmanb,1, Renata Pasqualinia,1, and Wadih Arapa,1 aDavid H. Koch Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; bHarvard Medical School and Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215; cStem Cell and Regeneration Program, Center for Neuroscience and Aging Research, Burnham Institute for Medical Research, La Jolla, CA 92037; dDepartment of Pediatrics, University of California, School of Medicine, La Jolla, CA 92093; and eSan Diego Consortium for Regenerative Medicine, La Jolla, CA 92037 Contributed by Richard L. Sidman, December 29, 2008 (sent for review October 13, 2008) Molecular and cellular interactions coordinating the origin and fate timeric complex functions as an integrated supramolecular of neural stem cells (NSCs) in the adult brain are far from being switch that regulates NSC fate. understood. We present a protein complex that controls prolifer- ation and migration of adult NSCs destined for the mouse olfactory Results and Discussion bulb (OB). Combinatorial selection based on phage display tech- Isolation of Peptides Binding to NSCs and Receptor Identification. We nology revealed a previously unrecognized complex between the profiled (16–18) the surface of a representative prototypical soluble protein netrin-4 and laminin ␥1 subunit that in turn clone of murine NSCs (C17.2) that can self-renew, differentiate activates an ␣61 integrin-mediated signaling pathway in NSCs. into all neural lineages, and populate developing or degenerating Differentiation of NSCs is accompanied by a decrease in netrin-4 regions of the central nervous system (19, 20). -
Cellular Changes in Injured Rat Spinal Cord Following Electrical Brainstem Stimulation
brain sciences Article Cellular Changes in Injured Rat Spinal Cord Following Electrical Brainstem Stimulation Walter J. Jermakowicz 1,* , Stephanie S. Sloley 2, Lia Dan 2, Alberto Vitores 2, Melissa M. Carballosa-Gautam 2 and Ian D. Hentall 2 1 Department of Neurological Surgery, University of Miami, 1095 NW 14th Terr, Miami, FL 33136, USA 2 Miami Project to Cure Paralysis, University of Miami, 1095 NW 14th Terr., Miami, FL 33136, USA; [email protected] (S.S.S.); [email protected] (L.D.); [email protected] (A.V.); [email protected] (M.M.C.-G.); [email protected] (I.D.H.) * Correspondence: [email protected]; Tel.: +1-615-818-3070 Received: 6 May 2019; Accepted: 27 May 2019; Published: 28 May 2019 Abstract: Spinal cord injury (SCI) is a major cause of disability and pain, but little progress has been made in its clinical management. Low-frequency electrical stimulation (LFS) of various anti-nociceptive targets improves outcomes after SCI, including motor recovery and mechanical allodynia. However, the mechanisms of these beneficial effects are incompletely delineated and probably multiple. Our aim was to explore near-term effects of LFS in the hindbrain’s nucleus raphe magnus (NRM) on cellular proliferation in a rat SCI model. Starting 24 h after incomplete contusional SCI at C5, intermittent LFS at 8 Hz was delivered wirelessly to NRM. Controls were given inactive stimulators. At 48 h, 5-bromodeoxyuridine (BrdU) was administered and, at 72 h, spinal cords were extracted and immunostained for various immune and neuroglial progenitor markers and BrdU at the level of the lesion and proximally and distally. -
Neuromodulation Shapes Interneuron Communication in the Mouse Striatum
From DEPARTMENT OF NEUROSCIENCE Karolinska Institutet, Stockholm, Sweden NEUROMODULATION SHAPES INTERNEURON COMMUNICATION IN THE MOUSE STRIATUM Matthijs Constantijn Dorst Stockholm 2020 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by US-AB © Matthijs Constantijn Dorst, 2020 ISBN 978-91-7831-908-4 Neuromodulation shapes interneuron communication in the mouse Striatum THESIS FOR DOCTORAL DEGREE (Ph.D.) By Matthijs Constantijn Dorst Principal Supervisor: Opponent: Professor Gilad Silberberg Professor Hagai Bergman Karolinska Institutet The Hebrew University of Jerusalem Department of Neuroscience Edmond & Lily Safra Center for Brain Sciences Co-supervisor(s): Examination Board: Professor Per Uhlén Professor Per Svenningsson Karolinska Institutet Karolinska Institutet Department of Medical Biochemistry and Department of Clinical Neuroscience Biophysics Division of Neuropharmacology - movement disorders Senior lecturer Karima Chergui Karolinska Institutet Department of Physiology and Pharmacology Division of Molecular Neurophysiology Professor Klas Kullander Uppsala Universitet Department of Neuroscience Research group Formation and Function of Neuronal Circuits Included Studies The following studies are included in this thesis, and will be referenced through- out the text as such: Study 1 Garas, F.N., Shah, R.S., Kormann, E., Doig, N.M., Vinciati, F., Nakamura, K.C., Dorst, M.C., Smith, Y., Magill, P.J. and Sharott, A., 2016. Sec- retagogin expression delineates functionally-specialized populations of striatal parvalbumin-containing interneurons. Elife, 5, p.e16088. Study 2 Lindroos, R., Dorst, M.C., Du, K., Filipović, M., Keller, D., Ketzef, M., Kozlov, A.K., Kumar, A., Lindahl, M., Nair, A.G., Pérez-Fernández, J., Grillner, S., Silberberg, G., Kotaleski, J.H., 2018. Basal Ganglia Neuromodulation Over Multiple Temporal and Structural Scales—Simulations of Direct Pathway MSNs Investigate the Fast Onset of Dopaminergic Effects and Predict the Role of Kv4. -
Slit Proteins: Molecular Guidance Cues for Cells Ranging from Neurons to Leukocytes Kit Wong, Hwan Tae Park*, Jane Y Wu* and Yi Rao†
583 Slit proteins: molecular guidance cues for cells ranging from neurons to leukocytes Kit Wong, Hwan Tae Park*, Jane Y Wu* and Yi Rao† Recent studies of molecular guidance cues including the Slit midline glial cells was thought to be abnormal [2,3]. family of secreted proteins have provided new insights into the Projection of the commissural axons was also abnormal: mechanisms of cell migration. Initially discovered in the nervous instead of crossing the midline once before projecting system, Slit functions through its receptor, Roundabout, and an longitudinally, the commissural axons from two sides of the intracellular signal transduction pathway that includes the nerve cord are fused at the midline in slit mutants [2,3]. Abelson kinase, the Enabled protein, GTPase activating proteins Because the midline glial cells are known to be important and the Rho family of small GTPases. Interestingly, Slit also in axon guidance, the commissural axon phenotype in slit appears to use Roundabout to control leukocyte chemotaxis, mutants was initially thought to be secondary to the cell- which occurs in contexts different from neuronal migration, differentiation phenotype [3]. suggesting a fundamental conservation of mechanisms guiding the migration of distinct types of somatic cells. In early 1999, results from three groups demonstrated independently that Slit functioned as an extracellular cue Addresses to guide axon pathfinding [4–6], to promote axon branching Department of Anatomy and Neurobiology, and *Departments of [7], and to control neuronal migration [8]. The functional Pediatrics and Molecular Biology and Pharmacology, Box 8108, roles of Slit in axon guidance and neuronal migration were Washington University School of Medicine, 660 S Euclid Avenue St Louis, soon supported by other studies in Drosophila [9] and in Missouri 63110, USA *e-mail: [email protected] vertebrates [10–14]. -
Netrin-1 Improves Adipose-Derived Stem Cell Proliferation, Migration, and Treatment Effect in Type 2 Diabetic Mice with Sciatic
Zhang et al. Stem Cell Research & Therapy (2018) 9:285 https://doi.org/10.1186/s13287-018-1020-0 RESEARCH Open Access Netrin-1 improves adipose-derived stem cell proliferation, migration, and treatment effect in type 2 diabetic mice with sciatic denervation Xing Zhang†, Jinbao Qin†, Xin Wang†, Xin Guo, Junchao Liu, Xuhui Wang, Xiaoyu Wu, Xinwu Lu* , Weimin Li* and Xiaobing Liu* Abstract Background: Diabetic peripheral neurovascular diseases (DPNVs) are complex, lacking effective treatment. Autologous/allogeneic transplantation of adipose-derived stem cells (ADSCs) is a promising strategy for DPNVs. Nonetheless, the transplanted ADSCs demonstrate unsatisfying viability, migration, adhesion, and differentiation in vivo, which reduce the treatment efficiency. Netrin-1 secreted as an axon guidance molecule and served as an angiogenic factor, demonstrating its ability in enhancing cell proliferation, migration, adhesion, and neovascularization. Methods: ADSCs acquired from adipose tissue were modified by Netrin-1 gene (NTN-1) using the adenovirus method (N-ADSCs) and proliferation, migration, adhesion, and apoptosis examined under high-glucose condition. The sciatic denervated mice (db/db) with type 2 diabetes mellitus (T2DM) were transplanted with N-ADSCs and treatment efficiency assessed based on the laser Doppler perfusion index, immunofluorescence, and histopathological assay. Also, the molecular mechanisms underlying Netrin-1-mediated proliferation, migration, adhesion, differentiation, proangiogenic capacity, and apoptosis of ADSCs were explored. Results: N-ADSCs improved the proliferation, migration, and adhesion and inhibited the apoptosis of ADSCs in vitro in the condition of high glucose. The N-ADSCs group demonstrated an elevated laser Doppler perfusion index in the ADSCs and control groups. N-ADSCs analyzed by immunofluorescence and histopathological staining demonstrated the distribution of the cells in the injected limb muscles, indicating chronic ischemia; capillaries and endothelium were formed by differentiation of N-ADSCs. -
Novel Roles for Slits and Netrins: Axon Guidance Cues As Anticancer Targets?
Nature Reviews Cancer | AOP, published online 17 February 2011; doi:10.1038/nrc3005 REVIEWS Novel roles for Slits and netrins: axon guidance cues as anticancer targets? Patrick Mehlen*, Céline Delloye-Bourgeois* and Alain Chédotal‡§|| Abstract | Over the past few years, several genes, proteins and signalling pathways that are required for embryogenesis have been shown to regulate tumour development and progression by playing a major part in overriding antitumour safeguard mechanisms. These include axon guidance cues, such as Netrins and Slits. Netrin 1 and members of the Slit family are secreted extracellular matrix proteins that bind to deleted in colorectal cancer (DCC) and UNC5 receptors, and roundabout receptors (Robos), respectively. Their expression is deregulated in a large proportion of human cancers, suggesting that they could be tumour suppressor genes or oncogenes. Moreover, recent data suggest that these ligand–receptor pairs could be promising targets for personalized anticancer therapies. Floor plate Netrin 1 — named from the sanscrit netr, ‘the one who roles of netrin 1 and its receptors have been extensively A group of cells that occupy guides’ — was purified by Tessier-Lavigne and col- described, but little is known about the function of these the ventral midline of the leagues as a soluble factor secreted by floor plate cells able other netrins. Netrin 4, which shares little homology developing vertebrate nervous to elicit the growth of commissural axons1,2. This discovery with netrin 1 (netrin 4, unlike other netrins, which dis- system, extending from the spinal cord to the launched a scientific race to identify novel secreted or play homology to the short arm of laminin-γ chains, is diencephalon. -
Role of Glucocorticoids in Tuning Hindbrain Stress Integration
The Journal of Neuroscience, November 3, 2010 • 30(44):14907–14914 • 14907 Cellular/Molecular Role of Glucocorticoids in Tuning Hindbrain Stress Integration Rong Zhang ( ),1,3 Ryan Jankord,1 Jonathan N. Flak,1 Matia B. Solomon,1 David A. D’Alessio,1,2 and James P. Herman1 Departments of 1Psychiatry and 2Internal Medicine, University of Cincinnati, Cincinnati, Ohio 45237, and 3Division of Endocrinology, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115 The nucleus of the solitary tract (NTS) is a critical integrative site for coordination of autonomic and endocrine stress responses. Stress-excitatory signals from the NTS are communicated by both catecholaminergic [norepinephrine (NE), epinephrine (E)] and non- catecholaminergic [e.g., glucagon-like peptide-1 (GLP-1)] neurons. Recent studies suggest that outputs of the NE/E and GLP-1 neurons of the NTS are selectively engaged during acute stress. This study was designed to test mechanisms of chronic stress integration in the paraventricular nucleus, focusing on the role of glucocorticoids. Our data indicate that chronic variable stress (CVS) causes downregu- lation of preproglucagon (GLP-1 precursor) mRNA in the NTS and reduction of GLP-1 innervation to the paraventricular nucleus of the hypothalamus. Glucocorticoids were necessary for preproglucagon (PPG) reduction in CVS animals and were sufficient to lower PPG mRNA in otherwise unstressed animals. The data are consistent with a glucocorticoid-mediated withdrawal of GLP-1 in key stress circuits. In contrast, expression of tyrosine hydroxylase mRNA, the rate-limiting enzyme in catecholamine synthesis, was increased by stress in a glucocorticoid-independent manner. These suggest differential roles of ascending catecholamine and GLP-1 systems in chronic stress, with withdrawal of GLP-1 involved in stress adaptation and enhanced NE/E capacity responsible for facilitation of responses to novel stress experiences. -
Netrin-1 Prolongs Skin Graft Survival by Inducing the Transformation of Mesenchymal Stem Cells from Pro-Rejection to Immune-Tolerant Phenotype
European Review for Medical and Pharmacological Sciences 2019; 23: 8741-8750 Netrin-1 prolongs skin graft survival by inducing the transformation of mesenchymal stem cells from pro-rejection to immune-tolerant phenotype L.- P. L IU1, W. CHEN2, Y. FAN2, B.-Y. QI2, Z. WANG2, B.-Y. SHI2 1Medical School of Chinese PLA, Beijing, China 2The Eighth Medical Center of PLA General Hospital, Beijing, China Lupeng Liu and Wen Chen contributed equally to this work Abstract. – OBJECTIVE: Mesenchymal stem MSC function. The immunohistochemistry re- cells (MSCs) induce allograft immune tolerance, sults showed that, compared with the rejection but low efficacy severely limits their wide appli- group, the T cell number in the skin graft signifi- cation. In this work, Netrin-1 was used to main- cantly decreased in the Netrin-1 group. tain MSC function in an IR environment to study CONCLUSIONS: MSC can be divided into im- its role in the immune tolerance induction of the mune-tolerant and pro-rejection types in or- allograft. gan transplantation and Netrin-1 can induce the MATERIALS AND METHODS: The experi- transformation of MSC from the pro-rejection to ments were divided into three groups: the con- immune-tolerant type and markedly prolong the trol group, the IR group and the Netrin-1 group skin graft survival time. (Netrin-1 was added to MSC medium and then cultured for 48 h). After digestion, MSCs were Key Words: mixed with TLR4 and TLR3 antibodies (BD), in- Mesenchymal stem cell, Transplantation, Netrin-1, cubated for 20 min, and washed with Phos- Immune tolerance. phate-Buffered Saline (PBS) three times. -
5 Shh Netrin Others
SYAPTIC PLASTICITY AND AXONAL GUIDANCE 1. The Neuron: basic Mechanisms of Action 2. Axon Guidance and Nerve Growth: Basic Principles 3. Short Range Guidance: 1. Eph-Ephrins / 2. Semaphorins 4. Long Range Cues: Semaphorins / Netrin-Slit / Nogo / Others 5. Learning and Memory - Guidance and Neuronal Adaptation in the Adult - Regulation of Pathways SLIT & NETRINS Netrins • Netrins are a small family of highly conserved guidance molecules (~70-80kDa). • One in worms (c.elegans) UNC6 • Two in Drosophila Netrin -A and -B • Two in chick, netrin-1 and -2. • In mouse and humans a third netrin identified netrin-3 (netrin-2-like). • In all species there are axons that project to the midline of the nervous system. • The midline attracts these axons and netrin plays a role in this. Netrins • Netrin-1 is produced by the floor plate • Netrin-2 is made in the ventral spinal cord except for the floor-plate • Both netrins become associated with the ECM and the receptor DCC • Model: commissural axons first encounter gradient of netrin-2, which brings them into the domain of netrin-1 Netrins Roof plate Commissural neuron 0 125 250 375 Commissural neurons extend ventrally Floor plate and then toward floor plate, if within 250µm from the floor plate Netrins • Netrins are bifunctional molecules, attracting some axons and repelling others. • C.elegans axons migrating away from the UNC-6 netrin source are misrouted in the unc-6 mutant. • The repulsive activity of netrin first shown in vertebrates for populations of motor axons that project away from the midline. • The receptors that mediate the attractive and repulsive effects of netrins are also highly conserved.