The Extracellular and Cytoplasmic Domains of Syndecan Cooperate Postsynaptically to Promote Synapse Growth at the Drosophila Neuromuscular Junction

The heparan sulfate proteoglycan (HSPG) Syndecan (Sdc) is a crucial regulator of synapse development and growth in both vertebrates and invertebrates. In Drosophila, Sdc binds via its extracellular heparan sulfate (HS) sidechains to the receptor protein tyrosine phosphatase LAR to promote the morphological growth of the neuromuscular junction (NMJ). To date, however, little else is known about the molecular mechanisms by which Sdc functions to promote synapse growth. Here we show that all detectable Sdc found at the NMJ is provided by the muscle, strongly suggesting a post-synaptic role for Sdc. We also show that both the cytoplasmic and extracellular domains of Sdc are required to promote synapse growth or to rescue Sdc loss of function. We report the results of a yeast two-hybrid screen using the cytoplasmic domains of Sdc as bait, and identify several novel candidate binding partners for the cytoplasmic domains of Sdc. Together, these studies provide new insight into the mechanism of Sdc function at the NMJ, and provide enticing future directions for further exploring how Sdc promotes synapse growth.

硫酸乙酰肝素蛋白聚糖（heparan sulfate proteoglycan, HSPG）黏结蛋白聚糖（Syndecan, Sdc）是脊椎动物与无脊椎动物突触发育与生长的关键调控因子。在果蝇（Drosophila）中，Sdc通过其胞外硫酸乙酰肝素（heparan sulfate, HS）侧链与受体蛋白酪氨酸磷酸酶LAR结合，以促进神经肌肉接头（neuromuscular junction, NMJ）的形态发生生长。然而迄今为止，学界对Sdc促进突触生长的分子机制仍知之甚少。本研究发现，神经肌肉接头处可检测到的所有Sdc均由肌肉细胞提供，这强烈提示Sdc发挥突触后功能。研究还证实，Sdc的胞质结构域与胞外结构域均为促进突触生长或挽救Sdc功能丧失所必需。本研究报道了以Sdc胞质结构域为诱饵进行的酵母双杂交筛选结果，并鉴定出数个全新的Sdc胞质结构域候选结合伴侣。综上，本研究为解析Sdc在神经肌肉接头处的作用机制提供了新视角，同时为进一步探索Sdc促进突触生长的具体途径指明了富有吸引力的未来研究方向。