The Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec H3A 2B4, Canada.
J Neurosci. 2012 May 2;32(18):6323-34. doi: 10.1523/JNEUROSCI.0916-12.2012.
Classical cadherins, which are adhesion molecules functioning at the CNS synapse, are synthesized as adhesively inactive precursor proteins in the endoplasmic reticulum (ER). Signal sequence and prodomain cleavage in the ER and Golgi apparatus, respectively, activates their adhesive properties. Here, we provide the first evidence for sorting of nonadhesive precursor N-cadherin (ProN) to the neuronal surface, where it coexists with adhesively competent mature N-cadherin (N-cad), generating a spectrum of adhesive strengths. In cultured hippocampal neurons, a high ProN/N-cad ratio downregulates synapse formation. Neurons expressing genetically engineered uncleavable ProN make markedly fewer synapses. The synapse number can be rescued to normality by depleting surface ProN levels through prodomain cleavage by an exogenous protease. Finally, prodomain processing is developmentally regulated in the rat hippocampus. We conclude that it is the ProN/N-cad ratio and not mature N-cad alone that is critical for regulation of adhesion during synaptogenesis.
经典钙黏蛋白是在中枢神经系统突触处发挥作用的黏附分子，它们在内质网（ER）中被合成成为黏附活性前体蛋白。在 ER 和高尔基体中，通过信号序列和原结构域的切割分别激活其黏附特性。在这里，我们首次提供了非黏附性前体 N 钙黏蛋白（ProN）分选到神经元表面的证据，在那里它与具有黏附能力的成熟 N 钙黏蛋白（N-cad）共存，产生一系列的黏附强度。在培养的海马神经元中，高 ProN/N-cad 比值下调突触形成。表达遗传工程不可切割的 ProN 的神经元形成的突触明显减少。通过外源性蛋白酶切割原结构域来耗尽表面 ProN 水平，可以将突触数量恢复到正常水平。最后，在大鼠海马中，原结构域的加工受到发育调控。我们得出结论，在突触发生过程中，调节黏附的关键因素是 ProN/N-cad 比值，而不仅仅是成熟的 N-cad。
