Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON, Canada M5S 3G5.
Neuroscience. 2012 Sep 6;219:255-70. doi: 10.1016/j.neuroscience.2012.05.069. Epub 2012 Jun 12.
The pyramidal neurons in the hippocampus are extremely neuroplastic, and the complexity of dendritic branches can be dynamically altered in response to a variety of stimuli, including learning and stress. Recently, the teneurin family of proteins has emerged as an interneuronal and extracellular matrix signaling system that plays a significant role in brain development and neuronal communication. Encoded on the last exon of the teneurin genes is a new family of bioactive peptides termed the teneurin C-terminal-associated peptides (TCAPs). Previous studies indicate that TCAP-1 regulates axon fasciculation and dendritic morphology in the hippocampus. This study was aimed at understanding the molecular mechanisms by which TCAP-1 regulates these changes in the mouse hippocampus. Fluoresceinisothiocyanate (FITC)-labeled TCAP-1 binds to the pyramidal neurons of the CA2 and CA3, and dentate gyrus in the hippocampus of the mouse brain. Moreover, FITC-TCAP-1 co-localizes with β-dystroglycan upon binding to the plasma membrane of cultured immortalized mouse E14 hippocampal cells. In culture, TCAP-1 stimulates ERK1/2-dependent phosphorylation of the cytoskeletal regulatory proteins, stathmin at serine-25 and filamin A at serine-2152. In addition, TCAP-1 induces actin polymerization, increases immunoreactivity of tubulin-based cytoskeletal elements and causes a corresponding increase in filopodia formation and mean filopodia length in cultured hippocampal cells. We postulate that the TCAP-1 region of teneurin-1 has a direct action on the cytoskeletal reorganization that precedes neurite and process development in hippocampal neurons. Our data provides novel evidence that functionally links the teneurin and dystroglycan systems and provides new insight into the molecular mechanisms by which TCAP-1 regulates cytoskeletal dynamics in hippocampal neurons. The TCAP-dystroglycan system may represent a novel mechanism associated with the regulation of hippocampal-function.
海马锥体神经元具有极强的神经可塑性，其树突分支的复杂性可以根据各种刺激（包括学习和压力）动态改变。最近，teneurin 蛋白家族已成为一种神经元内和细胞外基质信号系统，在大脑发育和神经元通讯中发挥重要作用。teneurin 基因的最后一个外显子编码了一种新的生物活性肽家族，称为 teneurin C 端相关肽（TCAPs）。先前的研究表明，TCAP-1 调节海马中的轴突聚集和树突形态。本研究旨在了解 TCAP-1 调节这些变化的分子机制。荧光素异硫氰酸酯（FITC）标记的 TCAP-1 与 CA2 和 CA3 及海马齿状回的锥体神经元结合。此外，FITC-TCAP-1 与培养的永生化小鼠海马细胞的质膜结合时与β-肌营养不良蛋白共定位。在培养物中，TCAP-1 刺激 ERK1/2 依赖性细胞骨架调节蛋白 stathmin 的丝氨酸-25 和 filamin A 的丝氨酸-2152 磷酸化。此外，TCAP-1 诱导肌动蛋白聚合，增加基于微管的细胞骨架成分的免疫反应性，并导致培养的海马细胞中丝状伪足形成和平均丝状伪足长度相应增加。我们假设 teneurin-1 的 TCAP-1 区域对海马神经元突起和突起发育之前的细胞骨架重排具有直接作用。我们的数据提供了新的证据，将 teneurin 和 dystroglycan 系统的功能联系起来，并深入了解 TCAP-1 调节海马神经元细胞骨架动力学的分子机制。TCAP- 肌营养不良蛋白系统可能代表与海马功能调节相关的新机制。
