Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2010 Oct 29;143(3):442-55. doi: 10.1016/j.cell.2010.09.038.
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.
已广泛研究促进兴奋性突触形成和成熟的机制。然而，限制兴奋性突触发育的分子事件，即确保突触在正确的时间和位置以及适当的数量形成的机制，还不太清楚。我们已经鉴定出一种 RhoA 鸟嘌呤核苷酸交换因子，Ephexin5，它负调控兴奋性突触的发育，直到 EphrinB 与 EphB 受体酪氨酸激酶结合触发 Ephexin5 的磷酸化、泛素化和降解。Ephexin5 的降解促进 EphB 依赖性兴奋性突触的发育，并由 Ube3A 介导，Ube3A 是一种在人类认知障碍 Angelman 综合征中发生突变的泛素连接酶，在某些形式的自闭症谱系障碍 (ASD) 中被复制。这些发现表明，突触发育过程中 EphB/Ephexin5 信号的异常可能导致 Angelman 综合征中出现异常的认知功能，并且可能在 ASD 中也会出现。
