Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia; Centre of Excellence in Genomics and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia.
Department of Biology, Swarthmore College, Swarthmore, PA, USA.
Brain Res Bull. 2018 Jun;140:5-18. doi: 10.1016/j.brainresbull.2018.03.013. Epub 2018 Mar 29.
Cell surface neural adhesion proteins are critical components in the complex orchestration of cell proliferation, apoptosis, and neuritogenesis essential for proper brain construction and behavior. We focused on the impact of two plasticity-associated IgLON family neural adhesion molecules, Neurotrimin (Ntm) and Limbic system associated membrane protein (Lsamp), on mouse behavior and its underlying neural development. Phenotyping neurons derived from the hippocampi of Lsamp, Ntm and LsampNtm mice was performed in parallel with behavioral testing. While the anatomy of mutant brains revealed no gross changes, the Ntm hippocampal neurons exhibited premature sprouting of neurites and manifested accelerated neurite elongation and branching. We propose that Ntm exerts an inhibitory impact on neurite outgrowth, whereas Lsamp appears to be an enhancer of the said process as premature neuritogenesis in Ntm neurons is apparent only in the presence of Lsamp. We also show interplay between Lsamp and Ntm in regulating tissue homeostasis: the impact of Ntm on cellular proliferation was dependent on Lsamp, and Lsamp appeared to be a positive regulator of apoptosis in the presence of Ntm. Behavioral phenotyping indicated test-specific interactions between Lsamp and Ntm. The phenotypes of single mutant lines, such as reduced swimming speed in Morris water maze and increased activity in the elevated plus maze, were magnified in LsampNtm mice. Altogether, evidence both from behavioral experiments and cultured hippocampal cells show combined and differential interactions between Ntm and Lsamp in the formation of hippocampal circuits and behavioral profiles. We demonstrate that mutual interactions between IgLON molecules regulate the initiation of neurite sprouting at very early ages, and even cell-autonomously, independent of their regulation of cell-cell adhesion.
细胞表面神经黏附蛋白是细胞增殖、凋亡和神经发生复杂协调的关键组成部分，这些过程对大脑结构和行为的正常发育至关重要。我们专注于两种与可塑性相关的 IgLON 家族神经黏附分子——神经调节素（Ntm）和边缘系统相关膜蛋白（Lsamp）对小鼠行为及其潜在神经发育的影响。我们平行进行 Lsamp、Ntm 和 LsampNtm 小鼠海马神经元的表型分析和行为测试。虽然突变体大脑的解剖结构没有明显变化，但 Ntm 海马神经元表现出神经突过早发芽，并表现出加速的神经突伸长和分支。我们提出 Ntm 对神经突生长有抑制作用，而 Lsamp 似乎是促进该过程的因素，因为只有在存在 Lsamp 的情况下，Ntm 神经元才会出现过早的神经发生。我们还展示了 Lsamp 和 Ntm 之间在调节组织平衡中的相互作用：Ntm 对细胞增殖的影响依赖于 Lsamp，而 Lsamp 在存在 Ntm 的情况下似乎是细胞凋亡的正调节剂。行为表型分析表明 Lsamp 和 Ntm 之间存在特定测试的相互作用。单突变系的表型，例如 Morris 水迷宫中游泳速度降低和高架十字迷宫中活动增加，在 LsampNtm 小鼠中更为明显。总之，来自行为实验和培养海马细胞的证据都表明，Ntm 和 Lsamp 在海马回路和行为特征的形成中存在联合和差异相互作用。我们证明，IgLON 分子之间的相互作用在非常早期的阶段，甚至是细胞自主的，独立于它们对细胞间黏附的调节，调节神经突发芽的启动。
