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.
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.
Lab Website: Margolis Lab
Schaffer TB, Smith JE, Cook EK, Phan T, Margolis SS. PKCε Inhibits Neuronal Dendritic Spine Development through Dual Phosphorylation of Ephexin5. Cell Rep. (2018) Nov 27;25(9):2470-2483.e8. doi: 10.1016/j.celrep.2018.11.005.
Ramachandran KV, Fu JM, Schaffer TB, Na CH, Delannoy M, Margolis SS. Activity-Dependent Degradation of the Nascentome by the Neuronal Membrane Proteasome. Mol Cell. (2018) Jul 5;71(1):169-177.e6. doi: 10.1016/j.molcel.2018.06.013.
Sell GL, Schaffer TB, Margolis SS. Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer's-like impairment in mice. J Clin Invest. (2017) May 1;127(5):1646-1650. doi: 10.1172/JCI85504.
Ramachandran KV, Margolis SS. A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function. Nat Struct Mol Biol. (2017) Apr;24(4):419-430. doi: 10.1038/nsmb.3389.