unbiased 发现 glypican 作为调节兴奋性突触发育的 LRRTM4 受体。
Unbiased discovery of glypican as a receptor for LRRTM4 in regulating excitatory synapse development.
机构信息
Neurobiology Section, Division of Biology, University of California San Diego, La Jolla, CA 92093, USA.
出版信息
Neuron. 2013 Aug 21;79(4):696-711. doi: 10.1016/j.neuron.2013.06.049. Epub 2013 Aug 1.
Abstract
Leucine-rich repeat (LRR) proteins have recently been identified as important regulators of synapse development and function, but for many LRR proteins the ligand-receptor interactions are not known. Here we identify the heparan sulfate (HS) proteoglycan glypican as a receptor for LRRTM4 using an unbiased proteomics-based approach. Glypican binds LRRTM4, but not LRRTM2, in an HS-dependent manner. Glypican 4 (GPC4) and LRRTM4 localize to the pre- and postsynaptic membranes of excitatory synapses, respectively. Consistent with a trans-synaptic interaction, LRRTM4 triggers GPC4 clustering in contacting axons and GPC4 induces clustering of LRRTM4 in contacting dendrites in an HS-dependent manner. LRRTM4 positively regulates excitatory synapse development in cultured neurons and in vivo, and the synaptogenic activity of LRRTM4 requires the presence of HS on the neuronal surface. Our results identify glypican as an LRRTM4 receptor and indicate that a trans-synaptic glypican-LRRTM4 interaction regulates excitatory synapse development.
摘要
富含亮氨酸重复序列（LRR）蛋白最近被鉴定为突触发育和功能的重要调节因子，但对于许多 LRR 蛋白，其配体-受体相互作用尚不清楚。在这里，我们使用一种无偏的基于蛋白质组学的方法鉴定了硫酸乙酰肝素（HS）蛋白聚糖聚糖作为 LRRTM4 的受体。聚糖以 HS 依赖性方式结合 LRRTM4，但不结合 LRRTM2。Glypican 4 (GPC4) 和 LRRTM4 分别定位于兴奋性突触的前突触和后突触膜上。与跨突触相互作用一致，LRRTM4 触发接触轴突中的 GPC4 聚类，并且 GPC4 以 HS 依赖性方式诱导接触树突中的 LRRTM4 聚类。LRRTM4 正向调节培养神经元和体内的兴奋性突触发育，并且 LRRTM4 的突触发生活性需要神经元表面存在 HS。我们的结果确定了聚糖作为 LRRTM4 的受体，并表明跨突触聚糖-LRRTM4 相互作用调节兴奋性突触发育。
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