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Seth S. Margolis, Ph.D.

Photo of Dr. Seth S. Margolis, Ph.D.

Assistant Professor of Biological Chemistry

Research Interests: Molecular mechanisms of synapse formation in development and disease

Background

Dr. Seth Margolis is an assistant professor of biological chemistry and neuroscience at the Johns Hopkins School of Medicine. His research focuses on the molecular mechanisms of synapse formation in development and disease.

Dr. Margolis and his team are currently researching Ephexin5 and new regulators of synapse formation.

He received his undergraduate degree in biochemistry from the University of Rochester and earned his Ph.D. from Duke University. He completed postdoctoral training in neurobiology at Harvard Medical School. Dr. Margolis joined the Johns Hopkins faculty in 2011.

His work has been recognized with several awards, including The Edward R. and Anne G. Lefler Postdoctoral Fellowship from 2009 to 2011.

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Titles

  • Assistant Professor of Biological Chemistry
  • Assistant Professor of Neuroscience

Education

Degrees

  • B.S., University of Rochester (New York) (1997)
  • Ph.D., Duke University (North Carolina) (2005)

Additional Training

Harvard Medical School, Boston, MA, 2011, Neurobiology

Research & Publications

Research Summary

Dr. Margolis' laboratory is focused on studying the molecular pathways that regulate excitatory synapse formation and investigating their relevance to the pathophysiology of cognitive disorders. Combining molecular biology, genetics, biochemistry and cell biological approaches in the mouse model system, they have discovered a molecular link between a major regulator of excitatory synapse development, EphB2, and Ube3A, an E3 ubiquitin ligase that is mutated in the human cognitive disorder Angelman Syndrome (AS) and duplicated in some forms of Autism Spectrum Disorders (ASDs). Their immediate goal is to further dissect and understand this EphB2/Ube3A interaction during non-pathological brain development. Their long-term goal is to address how, when these molecular pathways go awry, human cognitive disorders such as AS and ASDs develop.

Lab

Currently projects in Dr. Margolis' lab include studies of:

1) Ephexin5: Ephexin5 is a guanine nucleotide-exchange factor (GEF) that activates the small G-protein RhoA, a regulator of the actin cytoskeleton. Genetic loss- and gain-of-function studies indicate that Ephexin5 acts to restrict spine growth and synapse development in the developing brain. Upon induction of EphrinB/EphB ligand-receptor signaling, Ephexin5 is rapidly phosphorylated in an EphB-dependent manner and targeted for proteasome-dependent degradation. These findings suggest that Ephexin5 functions as a barrier to excitatory synapse development until its degradation is triggered by EphrinB binding to EphBs. Interestingly, the degradation of Ephexin5 is mediated by Ube3A, a ubiquitin ligase whose expression level is altered in the human cognitive disorder Angelman Syndrome (AS) and in some forms of autism. This suggests that aberrant EphB/Ephexin5 signaling during synaptic development may contribute to the abnormal cognitive function observed in AS and autism.

2) New regulators of synapse formation: The goal of this study will be to identify additional components of the genetic program that restrict synapse numbers using previously developed immunocytochemistry-based assay for neuronal synaptic connections in vitro. Specific targets will be corroborated using electrophysiological and in vivo morphological measurements. Dr. Margolis and his team are particularly interested in genes whose products function to restrict synapse formation early in development and are suggested to be defective or inappropriately activated in cognitive disorders.

Selected Publications

Margolis SS, Salogiannis J, Lipton DM, Mandel-Brehm C, Wills ZP, Mardinly AR, Hu L, Greer PL, Bikoff JB, Ho HY, Soskis MJ, Sahin M, Greenberg ME. "EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation." Cell. 2010 Oct 29;143(3):442-55. doi: 10.1016/j.cell.2010.09.038.

Nutt LK, Buchakjian MR, Gan E, Darbandi R, Yoon SY, Wu JQ, Miyamoto YJ, Gibbons JA, Andersen JL, Freel CD, Tang W, He C, Kurokawa M, Wang Y, Margolis SS, Fissore RA, Kornbluth S. "Metabolic control of oocyte apoptosis mediated by 14-3-3zeta-regulated dephosphorylation of caspase-2." Dev Cell. 2009 Jun;16(6):856-66. doi: 10.1016/j.devcel.2009.04.005. Erratum in: Dev Cell. 2010 Jan 19;18(1):165.Gibbon, Jennifer A [corrected to Gibbons, Jennifer A].

Guo JY, Yamada A, Kajino T, Wu JQ, Tang W, Freel CD, Feng J, Chau BN, Wang MZ, Margolis SS, Yoo HY, Wang XF, Dunphy WG, Irusta PM, Hardwick JM, Kornbluth S. "Aven-dependent activation of ATM following DNA damage." Curr Biol. 2008 Jul 8;18(13):933-42. doi: 10.1016/j.cub.2008.05.045. Epub 2008 Jun 19.

Wu Q, Guo Y, Yamada A, Perry JA, Wang MZ, Araki M, Freel CD, Tung JJ, Tang W, Margolis SS, Jackson PK, Yamano H, Asano M, Kornbluth S. "A role for Cdc2- and PP2A-mediated regulation of Emi2 in the maintenance of CSF arrest." Curr Biol. 2007 Feb 6;17(3):213-24.

Schafer ZT, Parrish AB, Wright KM, Margolis SS, Marks JR, Deshmukh M, Kornbluth S. "Enhanced sensitivity to cytochrome c-induced apoptosis mediated by PHAPI in breast cancer cells." Cancer Res. 2006 Feb 15;66(4):2210-8.

Activities & Honors

Honors

  • Protein Phosphatase Meeting Poster Award, Federation of American Societies for Experimental Biology (FASEB), 2004
  • Undergraduate Summer Research Scholar, Phytera Inc., 1995
  • George H. Hitchings Fund Fellowship for Health Research and Science Education, The Triangle Community Foundation, 2003 - 2004
  • The Edward R. and Anne G. Lefler Postdoctoral Fellowship, 2009 - 2011
  • Ruth L. Kirschstein National Research Service Award, 2006 - 2008
  • Science Program for Excellence in Science, AAAS, 2005
  • Pharmacology Departmental Symposium Poster Award, 2004
  • Graduate Student Symposium Speaker Award, 2003
  • Pharmacology Departmental Symposium Poster Award, 2002
  • Training Fellowship, NIH , 1999 - 2001
  • William Randolph Hearst Educational Endowment, 2000
  • Frank R. Lillie Fellowship and Scholarship Fund, 2000
  • Howard Hughes Medical Institute Summer Research Fellow, 1996

Professional Activities

  • Co-organizer, Cellular and Molecular Biology Program Retreat, The Johns Hopkins School of Medicine
    Annual Biochemistry
  • Faculty Search Committee, The Johns Hopkins School of Medicine, 2013 - 2012
    Biological Chemistry
  • Faculty Search Committee, The Johns Hopkins School of Medicine, 2013
    Brain Science Institute
  • Faculty Search Committee, The Johns Hopkins School of Medicine, 2013
    HIT Center
  • Graduate Student Recruiting, The Johns Hopkins School of Medicine, 2012
    Biochemistry, Cellular and Molecular Biology Program
  • Graduate Student Recruiting, The Johns Hopkins School of Medicine, 2012
    Biological Chemistry
  • Graduate Student Recruiting, The Johns Hopkins School of Medicine, 2012
    Neuroscience
  • M. Daniel Lane Lectureship Selection Committee, The Johns Hopkins School of Medicine, 2013
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