Richard E. Zigmond, Ph.D.

Richard E. Zigmond, Ph.D.
Professor
Department of Neurosciences
Case Western Reserve University


School of Medicine, Room E701
10900 Euclid Avenue
Cleveland OH, 44106-4975

Phone : (216) 368-4614
Fax : (216) 368-4650
Email : rez@case.edu
 
 

Lab details

RESEARCH INTERESTS

My laboratory studies plasticity in the adult nervous system. We are interested in the ways in which the chemistry of the adult nervous system can change and the functional consequences of such changes. We focus particularly on alterations that occur in response to (1) neural damage and (2) changes in the neural activity.

Currently, we are focusing on the molecules and cells involved in altering neuronal gene expression in response to axonal injury and in changing the intrinsic growth capacity of these neurons. Our studies focus on sympathetic and sensory neurons. Previous research has established that, when a peripheral neuron’s axon is severed, it decreases its synthesis of a number of proteins involved in neurotransmission and increases its synthesis of other proteins involved in regeneration. We find that, following axotomy, sympathetic neurons in the rat superior cervical ganglion express vasoactive intestinal peptide (VIP), galanin, and pituitary adenylate cyclase-activating polypeptide, three neuropeptides not normally expressed by these neurons. These changes are detected both at the peptide and mRNA levels.

Similar changes occur if adult ganglia are placed in either explant or dissociated cultures, allowing us to use these in vitro systems to study the molecular mechanisms involved. Our studies have shown that these changes in neuropeptide expression are triggered by the induction of cytokines of the gp130 family, including leukemia inhibitory factor (LIF) and IL-6 and by the reduction of the target-derived trophic factor nerve growth factor (NGF) all of which occur after transection of sympathetic axons. Strikingly, changes in these peptides occur in two other types of peripheral neurons after axonal injury, namely, sensory and motor neurons.

These two signals also are involved in triggering a growth response of the neurons to a conditioning lesion. We are currently using our findings to examine whether alterations in gp130 cytokine signaling plays a role in the deficit in regeneration known to occur in diabetes.

Another change which occurs in sympathetic and sensory ganglia after axotomy is the influx of macrophages. While macrophage accumulation in the distal stump of a transected peripheral nerve plays an important role in phagocytosing myelin and axonal debris, their role within peripheral ganglia is unknown and this question is an important part of our current research focus. Using two mutant mouse strains (the slow Wallerian degeneration mouse and a knockout for the chemokine receptors CCR2) we have found that preventation of macrophage accumulation in ganglia significantly inhibits the conditioning lesion response, indicating that these macrophages play an important role in the response of neurons to injury.

SELECTED PUBLICATIONS (since 1992)

  1. Niemi JP, DeFrancesco-Lisowitz A, Roldan-Hernandez L, Lindborg JA, Mandell D, Zigmond RE (2013)
    A critical role for macrophages near axotomized neuronal cell bodies in stimulating nerve renegration. J Neurosci 41:16236-16248 PubMed.
  2. Lingappa JR, Zigmond RE (2013)
    Limited recovery of pineal function after regeneration of preganglionic sympathetic axon: Evidence for loss of ganglionic synaptic specificity. J Neurosci 33:4867-4874 PubMed.
  3. Pellegrino MJ, Parris DC, Zigmond RE, Habecker BA (2011)
    Cytokines inhibit norepinephrine transporter expression by decreasing Hand2. Mol Cell Neurosci 46:671-680 PubMed.
  4. Hyatt Sachs H, Rohrer H, Zigmond RE (2010)
    The conditioning lesion effect on sympathetic neurite outgrowth is dependent on gp130 cytokines. Exp Neurol 223:516-22 PubMed.
  5. Habecker BA, Sachs HH, Rohrer H, Zigmond RE (2009)
    The dependence on gp130 cytokines of axotomy induced neuropeptide expression in adult sympathetic neurons. Dev Neurobiol 69:392-400 PubMed.
  6. Hyatt Sachs H, Schreiber RC, Shoemaker SE, Sabe A, Reed E, Zigmond RE (2007)
    Activating transcription factor 3 induction in sympathetic neurons after axotomy: response to decreased neurotrophin availability. Neuroscience 150:887-97 PubMed.
  7. Sachs HH, Wynick D, Zigmond RE (2007)
    Galanin plays a role in the conditioning lesion effect in sensory neurons. Neuroreport 18:1729-33 PubMed.
  8. Zigmond RE, Vaccariello SA (2007)
    Activating transcription factor 3 immunoreactivity identifies small populations of axotomized neurons in rat cervical sympathetic ganglia after transection of the preganglionic cervical sympathetic trunk. Brain Res 1159:119-23 PubMed.
  9. Shoemaker SE, Sachs HH, Vacariello SA, Zigmond RE (2006)
    Reduction in nerve growth factor availability leads to a conditioning lesion-like effect in sympathetic neurons. J Neurobiol 66:1322-1337 PubMed.
  10. Shoemaker SE, Sachs HH, Vaccariello SA, Zigmond RE (2005)
    A conditioning lesion enhances sympathetic neurite outgrowth. Exp Neurol 194:432-443 PubMed.
  11. Schreiber RC, Boeshore KL, Laube G, Veh RW, Zigmond RE (2004)
    Polyamines increase in sympathetic neurons and non-neuronal cells after axotomy and enhance neurite outgrowth in nerve growth factor-primed PC12 cells. Neuroscience 128:741-749.
  12. Boeshore KL, Schreiber RC, Vaccariello SA, Sachs HH, Salazar R, Lee J, Ratan RR, Leahy P, Zigmond RE (2004)
    Novel changes in gene expression following axotomy of a sympathetic ganglion: a microarray analysis. J Neurobiol 59:216-235.
  13. Nielsen KM, Chaverra M, Hapner SJ, Nelson BR, Todd V, Zigmond RE, Lefcort F (2004)
    PACAP promotes sensory neuron differentiation: blockade by neurotrophic factors. Mol Cell Neurosci 25:629-641.
  14. Schreiber RC, Vaccariello SA, Boeshore K, Shadiack AM, Zigmond RE (2002)
    A comparison of the changes in the non-neuronal cell populations of the superior cervical ganglia following decentralization and axotomy. J Neurobiol 53:68-79.
  15. Takasu MA, Dalva MB, Zigmond RE, Greenberg ME (2002)
    Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science 295:491-495.
  16. Zigmond RE (2001)
    Can galanin also be considered as growth-associated protein 3.2? Trends Neurosci 24:494-6.
  17. Schreiber RC, Krivacic K, Kirby B, Vaccariello SA, Wei T, Ransohoff RM, Zigmond RE (2001)
    Monocyte chemoattractant protein (MCP)-1 is rapidly expressed by sympathetic ganglion neurons following axonal injury. Neuroreport 12:601-606.
  18. Zhou Y, Deneris E, Zigmond RE (2001)
    Nicotinic acetylcholine receptor subunit proteins alpha7 and beta4 decrease in the superior cervical ganglion after axotomy. J Neurobiol 46:178-192.
  19. Shadiack AM, Sun Y, Zigmond RE (2001)
    Nerve growth factor antiserum induces axotomy-like changes in neuropeptide expression in intact sympathetic and sensory neurons. J Neurobiol 21:363-371.
  20. Bibevski S, Zhou Y, McIntosh JM, Zigmond RE, Dunlap ME (2000)
    Functional nicotinic acetylcholine receptors that mediate ganglionic transmission in cardiac parasympathetic neurons. J Neurosci 20:5076-5082.
  21. Zigmond RE (2000)
    Neuropeptide action in sympathetic ganglia. Evidence for distinct functions in intact and axotomized ganglia. Ann N Y Acad Sci 921:103-108.
  22. Ip NY, Zigmond RE (2000)
    Synergistic effects of muscarinic and secretin or vascoactive intestinal peptides on the regulation of tyrosine hydroxylase activity in the sympathetic neurons. J Neurobiol 42:14-2.
  23. Rittenhouse AR, Zigmond RE (1999)
    Role of N- and L-type calcium channels in depolarization-induced activation of tyrosine hydroxylase and release of norepinephrine by sympathetic cell bodies and nerve terminals. J Neurobiol 40:137-148.
  24. Nagamoto-Combs K, Vaccariello SA, Zigmond RE (1999)
    The levels of leukemia inhibitory factor mRNA in a Schwann cell line are regulated by multiple second messenger pathways. J Neurochem 72:1871-1881.
  25. Shadiack AM, Zigmond RE (1998)
    Galanin induced in sympathetic neurons after axotomy is anterogradely transported toward regenerating nerve endings. Neuropeptides 32:257-264.
  26. Mohney RP, Zigmond RE (1998)
    Vasoactive intestinal peptide enhances its own expression in sympathetic neurons after injury. J Neurosci 18:5285-5293.
  27. Shadiack AM, Vaccariello SA, Sun Y, Zigmond RE (1998)
    Nerve growth factor inhibits sympathetic neurons' response to an injury cytokine. Proc Natl Acad Sci U S A 95:7727-7730.
  28. Zhou Y, Deneris E, Zigmond RE (1998)
    Differential regulation of levels of nicotinic receptor subunit transcripts in adult sympathetic neurons after axotomy. J Neurobiol 34:164-178.
  29. Hyatt-Sachs H, Bachoo M, Screiber R, Vaccariello SA, Zigmond RE. (1996)
    Chemical sympathectomy and postganglionic nerve transection similarly increase galanin and VIP mRNA but not the peptides themselves. J Neurobiol 30:543-555.
  30. Sun Y, Zigmond RE (1996)
    Involvement of leukemia inhibitory factor in the increase in galanin and vasoactive intestinal peptide mRNA and the decrease in neuropeptide Y and tyrosine hydroxylase mRNA after axotomy of sympathetic neurons. J Neurochem 67:1751-1760.
  31. Sun Y, Zigmond RE (1996)
    Leukaemia inhibitory factor induced in the sciatic nerve after axotomy is involved in the induction of galanin in sensory neurons. Eur J Neurosci 8:2213-2220.
  32. Zigmond RE, Hyatt-Sachs H, Mohney RP, Schreiber RC, Shadiack AM, Sun Y, Vaccariello SA (1996)
    Changes in neuropeptide phenotype after axotomy of adult peripheral neurons and the role of leukemia inhibitory factor. Perspect Dev Neurobiol 4:75-90.
  33. Schreiber RC, Shadiack AM, Bennett TA, Sedwick CE, Zigmond RE (1995)
    Changes in the macrophage population of the rat superior cervical ganglion after postgangloinic nerve injury. J Neurobiol 27:141-153.
  34. Mohney RP, Siegel RE, Zigmond RE (1994)
    Galanin and vasoactive intestinal peptide messenger RNA expression increase following axotomy of the adult rat SCG. J Neurobiol 25:108-118.
  35. Sun Y, Rao MS, Zigmond RE, Landis SC (1994)
    Regulation of vasoactive intestinal peptide expression in sympathetic neurons in culture and after axotomy. The role of cholinergic differentiation factor/leukemia inhibitory factor. J Neurobiol 25:415-430.
  36. Hyatt-Sachs H, Schreiber RC, Bennett TA, Zigmond RE (1993)
    Phenotypic plasticity in adult sympathetic in vivo: Effect of deafferentation and axotomy on the expression of vasoactive intestinal peptide. J Neurosci 13:1624-1653.
  37. Rao MS, Sun Y, Escary JL, Perraeu J, Patterson PH, Zigmond RE, Brulet P, Landis SC (1993)
    Leukemia inhibitory factor mediates an injury response but not a development transmitter switch in sympathetic neurons. Neuron 11:1175-1185.
  38. Sun Y, Rao MS, Landis, Zigmond RE (1992)
    Depolarization increases vasoactive intestinal peptide- and substance P -like immunoreactivities in neonatal and adult sympathetic neurons. J Neurosci 12:3717-3728.

GRADUATE STUDENTS' FIRST AUTHOR PUBLICATIONS (Since 1992)

  1. Niemi JP, DeFrancesco-Lisowitz A, Roldan-Hernandez L, Lindborg JA, Mandell D, Zigmond RE (2013)
    A critical role for macrophages near axotomized neuronal cell bodies in stimulating nerve renegration. J Neurosci 41:16236-16248 PubMed.
  2. Shoemaker SE, Sachs HH, Vacariello SA, Zigmond RE (2006)
    Reduction in nerve growth factor availability leads to a conditioning lesion-like effect in sympathetic neurons. J Neurobiol 66:1322-1337 PubMed.
  3. Shoemaker SE, Sachs HH, Vaccariello SA, Zigmond RE (2005)
    A conditioning lesion enhances sympathetic neurite outgrowth. Exp Neurol 194:432-443 PubMed.
  4. Zhou Y, Deneris E, Zigmond RE (2001)
    Nicotinic acetylcholine receptor subunit proteins alpha7 and beta4 decrease in the superior cervical ganglion after axotomy. J Neurobiol 46:178-192.
  5. Bibevski S, Zhou Y, McIntosh JM, Zigmond RE, Dunlap ME (2000)
    Functional nicotinic acetylcholine receptors that mediate ganglionic transmission in cardiac parasympathetic neurons. J Neurosci 20:5076-5082.
  6. Ip NY, Zigmond RE (2000)
    Synergistic effects of muscarinic agonists and secretin or vasoactive intestinal peptide on the regulation of tyrosine hydroxylase activity in sympathetic neurons. J Neurobiol 42:14-21.
  7. Boeshore KL, Luckey CN, Zigmond RE, Large TH (1999)
    TrkB isoforms with distinct neurotrophin specificities are expressed in predominantly nonoverlapping populations of avian dorsal root ganglion neurons. J Neurosci 19:4739-4747.
  8. Mohney RP, Zigmond RE (1999)
    Galanin expression is decreased by cAMP-elevating agents in cultured sympathetic ganglia. Neuroreport 10:1221-1224.
  9. Mohney RP, Zigmond RE (1998)
    Vasoactive intestinal peptide enhances its own expression in sympathetic neurons after injury. J Neurosci 18:5285-5293.
  10. Zhou Y, Deneris E, Zigmond RE (1998)
    Differential regulation of levels of nicotinic receptor subunit transcripts in adult sympathetic neurons after axotomy. J Neurobiol 34:164-178.
  11. Sun Y, Zigmond RE (1996)
    Leukaemia inhibitory factor induced in the sciatic nerve after axotomy is involved in the induction of galanin in sensory neurons. Eur J Neurosci 8:2213-2220.
  12. Sun Y, Zigmond RE (1996)
    Involvement of leukemia inhibitory factor in the increases in galanin and vasoactive intestinal peptide mRNA and the decreases in neuropeptide Y and tyrosine hydroxylase mRNA in sympathetic neurons after axotomy. J Neurochem 67:1751-1760.
  13. Sun Y, Landis SC, Zigmond RE (1996)
    Signals triggering the induction of leukemia inhibitory factor in sympathetic superior cervical ganglia and their nerve trunks after axonal injury. Mol Cell Neurosci 7:152-163.
  14. Sun Y, Rao MS, Zigmond RE, Landis SC (1994)
    Regulation of vasoactive intestinal peptide expression in sympathetic neurons in culture and after axotomy: the role of cholinergic differentiation factor/leukemia inhibitory factor. J Neurobiol 25:415-430.
  15. Mohney RP, Siegel RE, Zigmond RE (1994)
    Galanin and vasoactive intestinal peptide messenger RNAs increase following axotomy of adult sympathetic neurons. J Neurobiol 25:108-118.
  16. Rao MS, Sun Y, Escary JL, Perreau J, Tresser S, Patterson PH, Zigmond RE, Brulet P, Landis SC (1993)
    Leukemia inhibitory factor mediates an injury response but not a target-directed developmental transmitter switch in sympathetic neurons. Neuron 11:1175-1185.
  17. Rao MS, Sun Y, Vaidyanathan U, Landis SC, Zigmond RE (1993)
    Regulation of substance P is similar to that of vasoactive intestinal peptide after axotomy or explantation of the rat superior cervical ganglion. J Neurobiol 24:571-580.
  18. Piszczkiewicz S, Zigmond RE (1992)
    Is the vasoactive intestinal peptide-like immunoreactivity in the rat pineal gland present in fibers originating in the superior cervical ganglion? Brain Res 598:327-331.
  19. Sun Y, Rao MS, Landis SC, Zigmond RE (1992)
    Depolarization increases vasoactive intestinal peptide- and substance P-like immunoreactivities in cultured neonatal and adult sympathetic neurons. J Neurosci 12:3717-3728.

POSTDOCS' FIRST AUTHOR PUBLICATIONS (Since 1993)

  1. Boeshore KL, Schreiber RC, Vaccariello SA, Sachs HH, Salazar R, Lee J, Ratan RR, Leahy P, Zigmond RE (2004)
    Novel changes in gene expression following axotomy of a sympathetic ganglion: a microarray analysis. J Neurobiol 59:216-235.
  2. Shadiack AM, Sun Y, Zigmond RE (2001)
    Nerve growth factor antiserum induces axotomy-like changes in neuropeptide expression in intact sympathetic and sensory neurons. J Neurobiol 21:363-371.
  3. Ip NY, Zigmond RE (2000)
    Synergistic effects of muscarinic agonists and secretin or vasoactive intestinal peptide on the regulation of tyrosine hydroxylase activity in sympathetic neurons. J Neurobiol 42:14-21.
  4. Rittenhouse AR, Zigmond RE (1999)
    Role of N- and L-type calcium channels in depolarization-induced activation of tyrosine hydroxylase and release of norepinephrine by sympathetic cell bodies and nerve terminals. J Neurobiol 40:137-148.
  5. Nagamoto-Combs K, Vaccariello SA, Zigmond RE (1999)
    The levels of leukemia inhibitory factor mRNA in a Schwann cell line are regulated by multiple second messenger pathways. J Neurochem 72:1871-1881.
  6. Shadiack AM, Zigmond RE (1998)
    Galanin induced in sympathetic neurons after axotomy is anterogradely transported toward regenerating nerve endings. Neuropeptides 32:257-264.
  7. Shadiack AM, Vaccariello SA, Sun Y, Zigmond RE (1998)
    Nerve growth factor inhibits sympathetic neurons' response to an injury cytokine. Proc Natl Acad Sci U S A 95:7727-7730.
  8. Shadiack AM, Vaccariello SA, Zigmond RE (1995)
    Galanin expression in sympathetic ganglia after partial axotomy is highly localized to those neurons that are axotomized. Neuroscience 65:1119-1127.
  9. Schulz DW, Kuchel GA, Zigmond RE (1993)
    Decline in response to nicotine in aged rat striatum: correlation with a decrease in a subpopulation of nicotinic receptors. J Neurochem 61:2225-2232.
  10. McKeon TW, Zigmond RE (1993)
    Vasoactive intestinal peptide and secretin produce long-term increases in tyrosine hydroxylase activity in the rat superior cervical ganglion. Brain Res 607:345-348.

 

STUDENTS' JOB PLACEMENT

Ph.D. StudentPresent Position
Chauncey W. Bowers, Ph.D.Musician Songwriter
CD available at chaunceybowers.com
Nancy Ip, Ph.D.Dean of Science
Department of Biochemistry
Hong Kong University of Science and Technology
Clear Water Bay
Kowloon, Hong Kong
Jaisri R. Lingappa, M.D., Ph.D.Associate Professor - Department of Global Health
Adjunct Associate Professor - Department of Medicine
Adjunct Associate Professor - Department of Microbiology
University of Washington
UW Box 358116
1616 Eastlake Avenue East
Suite 300
Seattle, WA 98102
Michael Schwarzschild, M.D., Ph.D.Professor of Neurology
Harvard Medical School
MassGeneral Institute for Neurodegenerative Disease
Massachusetts General Hospital
Room No.3002, 114 16th Street
Charlestown MA 02129
Yi Sun, Ph.D.Associate Professor
Department of Psychiatry and Biobehavioral Sciences
UCLA Medical School
Los Angeles, CA 90095-7332
Robert P. Mohney, Ph.D.Director of Project Management (Academics)
Metabolon Inc.
617 Capitola Drive, Suite 400
Durham, NC 27713
Yuefang Zhou, Ph.D.Staff Scientist
Washington University School of Medicine
Department of Ophthalmology and Visual Sciences
660 S. Euclid Avenue
St. Louis, MO 63110
Sarah E Shoemaker, Ph.D.Research Mentorship Coordinator
NC School of Science and Mathematics
Durham, NC
Jon P. NiemiCurrent Graduate Student
Jane A. LindborgCurrent Graduate Student

 

POSTDOCS' JOB PLACEMENT

Postdoc / R.A.Present Position
Alcmene Chalazonitis, Ph.D.Senior Research Scientist
Department of Pathology and Cell Biology
Columbia University CPS
630 W. 168th Street
New York NY 10032
Vincent A. Chiappinelli, Ph.D.Chair and Professor of Pharmacology
Dept. of Pharmacology
George Washington University School of Medicine
2300 Eye Street NW
Washington DC 20037
Ralph H. Loring, Ph.D.Associate Professor
Department of Pharmaceutical Sciences
Northeastern University
211 Mugar Hall
Boston MA 02215
Ann R. Rittenhouse, Ph.D.Associate Professor
Dept. of Microbiology and Physiological Science
University of Massachusetts Medical Center
368 Plantation Street
Worcester MA 01605
Cathrine A. Sasek, Ph.D.Health Scientist Administrator
National Institute on Drug Abuse
6001 Executive Blvd
Rockville MD 20852
George A. Kuchel, MD, FRCPCProfessor of Medicine
Citicorp Chair in Geriatrics & Gerontology
Director, UConn Center on Aging
Chief, Division of Geriatric Medicine
University of Connecticut Health Center
263 Farmington Avenue, MC-5215
Farmington, CT 06030-5215
David W. Schulz, Ph.D.Senior Director - Worldwide Business Development
Pfizer Inc.
445 Eastern Point Rd.
Groton CT 06340
Annette M. Shadiack, Ph.D. Senior Director, Nonclinical Development
Elusys Therapeutics Inc.
25, Riverside Drive-Unit 1
Pine Brook, NJ 07058
Kumi Nagomoto-Combs, Ph.D.Assistant Professor
Department of Anatomy and Cell Biology
University of North Dakota
School of Medicine and Health Science
Grand Forks, ND 58203-2812
Kristen Boeshore, Ph.D.Assistant Professor
Biology Department
Lebanon Valley College
101 N. College Ave.
Annville, PA 17003

 

UNDERGRADUATES' JOB PLACEMENT

Undergraduate StudentPresent Position
Thomas Rando, MD, Ph.D.Professor
Department of Neurology and Neuroscience
Stanford University School of Medicine
Stanford, CA 94305-5253
Gabrielle Leblanc, Ph.D.Senior Technical Editor
Biosciences Division
SRI International
333 Ravenwood Ave.
Menlo Park
CA 94025-3493
Usha (Vaidyanathan) Stiefel, MD Assistant Professor
Case Western Reserve University School of Medicine
Chief, Infectious Diseases Section
Cleveland VAMC
Cleveland, Ohio
Caitlin Sedwick, Ph.D.Freelance Science Writer
csedwick@gmail.com
Christine M. LaPash Daniels, Ph.D.Research Associate
Waisman Cancer
University of Wisconsin-Madison
1500 Highland Ave. Rm 713A
Madison WI 53705
Elliot SchwartzMedical Student
Case Western Reserve University
School of Medicine

 

RESEARCH ASSISTANTS' JOB PLACEMENT

Research AssistantPresent Position
Claire BaldwinFreelance Science Writer
Consultant editor, 761 Federal St
Belchertown, MA 01007
claire.baldwin123@gmail.com
Peter Rice PharmD, Ph.D.Professor
Department of Clinical Pharmacy
University of Colorado
Denver, CO
Lisa Dahm Ph.D.Director, Clinical Informatics
Director, ICTS Center for Biomedical Informatics
UC Irvine Health Information Services
University of California, Irvine
Rebecca SchreiberPapercut Artist
Paper Confections Design
www.paperconfections.com
Stacey KoethSales Representative/Floor Design
Nature Stone
Hilary SachsSenior Professional Research Assistant
University of Colordo, AMC
Cell and Developmental Biology, Denver, CO

 

 
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