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Frank L Margolis
 

Frank L Margolis Ph.D.

Academic Title: Professor
Primary Appointment: Anatomy and Neurobiology
Secondary Appointments: Psychiatry
Additional Title(s): Director, MS Program in Molecular Medicine
fmargoli@umaryland.edu
Location: HSFII, S203-D
Phone: (410) 706-8913
Phone: (410) 706-8914
Fax: (410) 706-2512
Lab: (410) 706-8821

Personal History:

Education

  • Antioch College, Yellow Springs, OH, 1954-1959, B.S. Chemistry
  • Columbia U., New York City, NY, 1959-1964, Ph.D. Biochemistry
  • Columbia U., New York City, NY, 1964-1965, Postdoctorate, Biochem.
  • Lab de Physiologie Comp, Universiti de Paris, 1965-1966, Postdoctorate, Fetal endocrinology

Positions and Employment

  • 1966-1969: Asst. Res. Microbiologist, Dept. of Med. Microbiol. and Immunol., UCLA Sch. of Med., Los Angeles
  • 1969-1971: Research Assoc., Roche Institute of Molecular Biology
  • 1971-1973: Asst. Member, Roche Institute of Molecular Biology .
  • 1972-1995: Adjunct Professor, Graduate Program in Biochemistry, CUNY
  • 1974-1980: Associate Member, Roche Institute of Molecular Biology .
  • 1981-1995: Full Member, Roche Institute of Molecular Biology
  • 1987-1988: Acting Chairman, Dept of Neurosci, Roche Institute of Molecular Biology
  • 1988-1995: Head, Lab. Chemosensory Neurobiology, Roche Institute of Molecular Biology
  • 1995-present: Professor, Dept. of Anatomy and Neurobiology, University of Maryland, Baltimore.
  • 2005- present: Professor, Dept of Psychiatry, University of Maryland, Baltimore

Research Interests:

The vertebrate olfactory system is an extremely plastic neurobiological substrate that provides a platform from which one can address questions relating to sensory transduction, neuronal ontogeny, plasticity, regeneration and transynaptic regulation of gene expression. One of the major goals of my laboratory is to identify and characterize the molecular mechanisms responsible for regulating olfactory neuron gene expression, and to learn how they contribute to the formation, organization and function of this critical chemosensory system.

We use a multidisciplinary strategy emphasizing biochemical and molecular biological approaches. Promoter motifs involved in regulating olfactory neuron gene expression have been characterized in vitro by gel-shift and footprinting analyses and in vivo by the generation of transgenic mice using truncated and mutated promoter constructs. This latter approach has been used to selectively engineer heterologous gene expression in olfactory neurons.

Primary olfactory neurons are constantly being replaced from a population of precursor cells in the nasal neuroepithelium. These new neurons reinnervate the olfactory bulb. Two questions that arise as a result of this observations are 1) Is reinnervation topographically correct? 2) What are the mechanisms that participate in this process? To address the former we have used transgenic mice expressing the lacZ gene in a subset of cells to demonstrate, for the first time, that reinnervation of the bulb after deafferentation is topographically correct. To address the second question we have begun to characterize the patterns of expression during development and in response to lesion of the BMP family of cytokines and their modulators (noggin, chordin, follistatin and tolloid). These molecules are differentially expressed in various neuronal populations in the olfactory system in spatial and temporal patterns that implies that they participate in development and reorganization of this system. these processes. This is a new and active direction for the laboratory.

An ongoing question in the lab is the function of OMP, a novel phylogenetically conserved, cytoplasmic protein. To this end we have created "knock-out" mice. These mice are superficially normal, but manifest reduced olfactory neural activity. This is evident both electrophysiologically and behaviorally. These observations imply that OMP is a novel regulator of olfactory signal detection/transduction. To address this we are utilizing electrophysiological, behavioral and biochemical approaches. We have "rescued" the electrophysiological phenotype by transfection of olfactory neurons with OMP expressing adenovirus. Attempts to do the same for the behavioral deficit are underway. Biochemical approaches to this problem include the use of 1)solution NMR to determine the 3-D structure of OMP, 2)biochemical studies of protein-protein interaction and 3) phage display to identify and characterize the molecular components responsible for the phenotype observed.

Lab Techniques and Equipment:

We utilize a range of biochemical, molecular and anatomical techniques in the lab such as 1) protein characterization by isolation, western blotting and cross linking, 2) cDNA cloning, RT-PCR, phage display and protein expression and 3) in situ hybridization, histology and immunocytochemistry. Behavioral and electrophysiological studies are by collaboration.


Laboratory Personnel:

  • Jae Hyung Koo Ph.D.
    Project: Characterization of the Bex proteins-interacting partners to the OMP protein.
    jkoo001@umaryland.edu
  • Hyun Jung Kwon, Ph.D.
    Project: Functional analysis ofthe OMP-null mouse by calcium imaging.
    hkwon001@umaryland.edu
  • Maria Ukhanova Ph.D.
    Project: Characterization of BMP and noggin expression in mouse olfactory system.
    mukha001@umaryland.edu
  • Joyce Margolis M.A.
    Project: Evaluation of the function of Bex, Determination of the expression splice variants of sodium/calcium exchangers.
    jmargoli@umaryland.edu
  • Faith Scipio
    Project: Genotyping and oversight of transgenic and KO mouse lines.
    fscip001@umaryland.edu
  • Hyun Hee Kim M.S.
    Project: Changes in gene expression in piriform cortex following peripheral olfactory deafferentation.
    hkim011@umaryland.edu

Grants and Contracts:

ABMRF
F.L. Margolis (PI)

Current 6/01/06-5/31/08
Title: Neuronal loss and replacement after ethanol and abstinence.
Goal: The major goal of this grant is to determine the effect of ethanol administration on olfactory neuron loss and recovery in control and transgenic mice.

5R01 DC03112
F.L. Margolis (PI)
Current 04/01/97-08/31/12
NIH/NIDCD Title: OMP: Role in olfactory signal detection and transduction
Goals: The major goals of this project are to identify and characterize the biochemical mechanism by which OMP functions, to identify partner molecules and to characterize and rescue the phenotype of the OMP-null mutant.


Publications:

Youngentob, S. and Margolis F.L.: OMP gene causes an elevation in behavioral threshold sensitivity. Neuroreport 10: 15-19 (1999).

Baumeister H., Gronostajski, R.M., Lyons G.E., Margolis F.L.: Identification of NFI-binding sites and cloning of NFI-cDNAs suggest a regulatory role for NFI transcription factors in olfactory neuron gene expression. Brain Res. Mol. Brain Res. 72: 65-79 (1999).

Baker H., Cummings D.M., Munger S.D., Margolis J.W., Franzen L., Reed R.R., and Margolis F.L.: Targeted deletion of a cyclic nucleotide-gated channel subunit (OCNC1): biochemical and morphological consequences in adult mice.  J. Neurosci.19: 9313-9321 (1999).

Cummings, D.M., Emge D.K., Small, S.L. and Margolis, F.L.: The pattern of olfactory bulb re-innervation returns following recovery from reversible peripheral deafferentation. J. Comp. Neurol. 421:362-73 (2000).

Ivic L., Pyrski M.M., Margolis J.W., Richards L.J., Firestein, S., Margolis, F.L.: Adenoviral vector-mediated rescue of the OMP-null phenotype in vivo.  Nature Neurosci. 11:1113-1120. (2000).

Behrens, M., Venkatraman, G., Gronostajski, R.M., Reed, R.R. and Margolis F.L.:  NFI in the development of the olfactory neuroepithelium and the regulation of the olfactory marker protein (OMP) expression.  Eur. J. Neuroscience. 12:1372-84 (2000).

Baldisseri, D.M., Margolis, J.W., Omotosho P.A. and Margolis F.L.:  Sequence-specific NMR resonance assignments of the backbone atoms for the olfactory marker protein, OMP. J. Biomolecular NMR 17:353-354 (2000).

Pyrski M, Xu Z, Walters E, Gilbert DJ, Jenkins NJ, Copeland NJ, and Margolis FL: The OMP-lacZ transgene mimics the unusual expression pattern of OR-Z6, a new odorant receptor gene on mouse chromosome 6: implication for locus-dependent gene-expression. J. Neurosci.: 21: 4637-4648 (2001).

D.H. Schulze, A. Ruknudin, J.W. Margolis, S.K. Polumuri, F.L. Margolis, Sodium Calcium Exchangers in Olfactory Tissue. "Cellular and molecular physiology of Sodium-Calcium exchange," Banff, October, (2001).

Baldisseri DM, Margolis JW, Weber DJ, Koo JH, Margolis FL. Olfactory marker protein (OMP) exhibits a beta-clam fold in solution.  Implications for target peptide interaction and olfactory signal transduction. J Molec Biol 319:823-837 (2002).

Perretto, P Cummings, DM, Modena C,  Behrens M,  Venkatraman G, Fasolo A, Margolis FL: BMP mRNA and protein expression in the developing mouse olfactory system J. Comp. Neurol. 451:267-278 (2002).

Schulze DH, Pyrski M, Ruknudin A, Margolis JW,  Polumuri SK, Margolis FL. Sodium-calcium exchangers in olfactory tissue.  in Lytton J, Schnetkamp PPM, Hryshko LV and Blaustein MP (Editors) "Cellular and molecular physiology of sodium-calcium exchange" Ann. NY Acad. Sci. 976, 67-72 (2002).

Behrens, M, Margolis JW, and Margolis FL. Identification of members of the Bex gene family as olfactory marker protein (OMP) binding partners. J Neurochem 86, 1289-1296 (2003).

McBride K, Slotnick B, Margolis FL. Does Intranasal Application of Zinc Sulfate Produce Anosmia in the Mouse? An Ofactometric and Anatomical study. Chem Senses 28, 659-670 (2003).

Youngentob SL, P.F. Kent PF and Margolis FL. OMP Gene Deletion Results in an Alteration in Odorant-Induced Mucosal Activity Patterns. J. Neurophysiol. 90, 3864-3873.(2003)

Koo JH, Gill S, Pannell L, Menco B and Margolis FL. The interaction of Bex and OMP reveals a metabolically active covalent dimer of OMP. J. Neurochem. In press (2004).

Youngentob S. Pyrski, M. and Margolis FL. Adenoviral vector-mediated rescue of the OMP-null behavioral phenotype: Enhancement of odorant threshold sensitivity. Behavioral Neuroscience. In press (2004).

Youngentob SL, Pyrski MM, Margolis FL. Adenoviral vector-mediated rescue of the OMP-null behavioral phenotype: enhancement of odorant threshold sensitivity. Behav Neurosci. 2004 118:636-42.

Koo JH, Gill S, Pannell LK, Menco BP, Margolis JW, Margolis FL. The interaction of Bex and OMP reveals a dimer of OMP with a short half-life. J Neurochem. 2004 90:102-16.

Peretto P, Dati C, De Marchis S, Kim HH, Ukhanova M, Fasolo A, Margolis FL. Expression of the secreted factors noggin and bone morphogenetic proteins in the subependymal layer and olfactory bulb of the adult mouse brain. Neuroscience. 2004;128:685-96.

Koo JH, Saraswati M, Margolis FL. Immunolocalization of Bex protein in the mouse brain and olfactory system. J Comp Neurol. 2005 487:1-14.

Gitti RK, Wright NT, Margolis JW, Varney KM, Weber DJ, Margolis FL. Backbone dynamics of the olfactory marker protein as studied by 15N NMR relaxation measurements. Biochemistry. 2005 44:9673-9.

Gitti RK, Wright NT, Margolis JW, Varney KM, Weber DJ, Margolis FL. Backbone dynamics of the olfactory marker protein as studied by 15N NMR relaxation measurements. Biochemistry. 2005 44:9673-9.

Bernstein SL, Koo JH, Slater BJ, Guo Y, Margolis FL. Analysis of optic nerve stroke by retinal Bex expression. Mol Vis. 2006 12:147-55.

Venkatraman G, Behrens M, Pyrski M, Margolis FL. Expression of Coxsackie-Adenovirus receptor (CAR) in the developing mouse olfactory system. J Neurocytol. 2005 34:295-305.

Kim HH, Puche AC, Margolis FL. Odorant deprivation reversibly modulates transsynaptic changes in the NR2B-mediated CREB pathway in mouse piriform cortex. J Neurosci. 2006 26:9548-59.

Pyrski M, Koo JH, Polumuri SK, Ruknudin AM, Margolis JW, Schulze DH, Margolis FL. Sodium/calcium exchanger expression in the mouse and rat olfactory systems. J Comp Neurol. 2007 501:944-58.

Bettini E, Margolis FL. Expression of an intron-containing beta-tubulin mRNA in catfish olfactory epithelium. J Mol Histol. 2007 Sep 12; [Epub ahead of print]

Koo JH, Smiley MA, Lovering RM, Margolis FL. Bex1 knock out mice show altered skeletal muscle regeneration. Biochem Biophys Res Commun. 2007 363:405-10.

Reisert J, Yau KW, Margolis FL. Olfactory marker protein modulates the cAMP kinetics of the odour-induced response in cilia of mouse olfactory receptor neurons. J Physiol. 2007 585:731-40.