EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation

Seth S. Margolis, John Salogiannis, David M. Lipton, Caleigh Mandel-Brehm, Zachary P. Wills, Alan R. Mardinly, Linda Hu, Paul L. Greer, Jay B. Bikoff, Hsin Yi Henry Ho, Michael J. Soskis, Mustafa Sahin, Michael E. Greenberg

Research output: Contribution to journalArticle

Abstract

The mechanisms that promote excitatory synapse formation and maturation have been extensively studied. However, the molecular events that limit excitatory synapse development so that synapses form at the right time and place and in the correct numbers are less well understood. We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. The degradation of Ephexin5 promotes EphB-dependent excitatory synapse development and is mediated by Ube3A, a ubiquitin ligase that is mutated in the human cognitive disorder Angelman syndrome and duplicated in some forms of Autism Spectrum Disorders (ASDs). These findings suggest that aberrant EphB/Ephexin5 signaling during the development of synapses may contribute to the abnormal cognitive function that occurs in Angelman syndrome and, possibly, ASDs.

Original languageEnglish (US)
Pages (from-to)442-455
Number of pages14
JournalCell
Volume143
Issue number3
DOIs
StatePublished - Oct 29 2010
Externally publishedYes

Keywords

  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Margolis, S. S., Salogiannis, J., Lipton, D. M., Mandel-Brehm, C., Wills, Z. P., Mardinly, A. R., Hu, L., Greer, P. L., Bikoff, J. B., Ho, H. Y. H., Soskis, M. J., Sahin, M., & Greenberg, M. E. (2010). EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell, 143(3), 442-455. https://doi.org/10.1016/j.cell.2010.09.038