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

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.

Pubmed ID: 21029865


  • 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



Publication Data

October 29, 2010

Associated Grants

  • Agency: NIA NIH HHS, Id: 5T32AG00222-15
  • Agency: NINDS NIH HHS, Id: R01 5R01NS045500
  • Agency: NINDS NIH HHS, Id: R01 NS045500

Mesh Terms

  • Angelman Syndrome
  • Animals
  • Child
  • Child Development Disorders, Pervasive
  • Dentate Gyrus
  • Embryo, Mammalian
  • Gene Knockout Techniques
  • Humans
  • Mice
  • Rats
  • Rats, Long-Evans
  • Receptors, Eph Family
  • Synapses
  • Ubiquitin-Protein Ligases
  • rhoA GTP-Binding Protein