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Seth Margolis Portrait

Seth Margolis
Assistant Professor of Biological Chemistry
Johns Hopkins University School of Medicine


725 N. Wolfe Street, 517 WBSB
Baltimore, MD 21205
Office Phone: 410-502-5362
Lab Phone: 410-955-2362
Fax: 410-955-5759
Email: smargol7@jhmi.edu
Lab Web Site

Click Here for PDF of CV

Molecular Mechanisms of Synapse Formation in Development and Disease

Synapses are specialized cell-cell junctions which connect individual neurons together and are the sites of transmission of information between neurons.  While the molecular mechanisms which promote synapse formation have been a subject of intense investigation, little is known about the molecular mechanisms that limit synapse formation so that synapses form at the right time and place and in the correct numbers.  We hypothesize that this step in the refinement of synaptic formation is crucial for the fine-tuning of neuronal connectivity and that signaling networks which limit synapses during development are either defective or inappropriately activated in cognitive disorders. Accordingly, our laboratory studies the signaling pathways that regulate synapse formation during normal brain development to begin to understand how, when these pathways go awry, human cognitive disorders develop.

Currently projects 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. 

Using Ephexin5 our laboratory will pursue an understanding of the molecular pathways that regulate restriction of excitatory synapse formation and their relevance to the pathophysiology of Angelman Syndrome by addressing the following questions:

1) What are the molecular determinants critical for Ube3A-mediated control of Ephexin5 degradation?

2) What molecular and cellular events underlie Ephexin5-mediated excitatory synapse restriction important for basic wiring of the nervous system? 

3) What additional substrates of Ube3A are important for synapse formation?

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.  We 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.

Recent Publications

Margolis SS*, Salogiannis J*, Lipton DM, Mandel-Brehm C, Wills ZP, Mardinly AR, Hu L, Greer PL, Bikoff JB, Ho H-YH, Soskis, MJ , Sahin M, Greenberg ME . EphB mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell. 2010 Nov 29; 143 (4): 442-55.
PubMed Reference
 

Comment in “Cell”: Dalva MB. (2010) Ephecting excitatory synapse development. Cell. 29;143(3):341-2.
PubMed Reference


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