Neurexin Superfamily Cell Membrane Receptor Contactin-Associated Protein Like-4 (Cntnap4) Is Involved in Neural EGFL-Like 1 (Nell-1)-Responsive Osteogenesis.
Neurexin Superfamily Cell Membrane Receptor Contactin-Associated Protein Like-4 (Cntnap4) Is Involved in Neural EGFL-Like 1 (Nell-1)-Responsive Osteogenesis.
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神经毒素超家族细胞膜受体接触蛋白相关的蛋白像-4（CNTNAP4）参与神经EGFL样1（NELL-1）反应性成骨。
DOI：
10.1002/jbmr.3524
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Soo C
中科院分区：
文献类型：
--
作者：
Li C;Zheng Z;Ha P;Chen X;Jiang W;Sun S;Chen F;Asatrian G;Berthiaume EA;Kim JK;Chen EC;Pang S;Zhang X;Ting K;Soo C
Contactin 相关蛋白样 4 (Cntnap4) 是跨膜分子神经素超家族的成员，在神经元细胞通讯中具有关键功能。 Cntnap4 敲除小鼠表现出突触前 γ-氨基丁酸 (GABA) 减少和多巴胺释放增加，这与人类自闭症谱系障碍患者中常见的严重、高度渗透、重复和持久运动相关。然而，除了神经系统之外，Cntnap4 的已知功能尚未被揭示。同时，已知分泌蛋白神经 EGFL 样 1 (Nell-1) 在多种小型和大型动物模型中发挥有效的成骨作用，而不会出现骨形态发生蛋白 2 常见的脱靶效应。在这项研究中，在成骨过程中寻找 Nell-1 特异性细胞表面受体时，我们通过证明以下方法鉴定并验证了 Nell-1 和 Cntnap4 之间的配体/受体样相互作用：1) Nell-1 和 Cntnap4 共定位在成骨定向细胞的表面； 2）Nell-1与Cntnap4之间的高亲和力相互作用； 3) 通过 Cntnap4 敲低消除 Nell-1 响应性 Wnt 和 MAPK 信号转导以及成骨作用； 4) 在 Wnt1-Cre 介导的 Cntnap4 敲除转基因小鼠中，在 Nell-1 缺陷小鼠中观察到颅骨锁骨发育不良样缺陷的复制。总的来说，这些发现表明 Cntnap4 在 Nell-1 响应性成骨中发挥着关键作用。此外，这是 Cntnap4 在肌肉骨骼系统中的第一个功能注释。有趣的是，Nell-1 和 Cntnap4 也共定位于人类海马中间神经元的表面，这表明 Nell-1 是神经系统中 Cntnap4 的潜在新型配体。 Nell-1 和 Cntnap4 之间的配体/受体样相互作用的这种意想不到的特征表明 Nell-1 和 Cntnap4 在成骨以及潜在的神经发育和功能中具有新的生物功能轴。
Contactin-associated protein-like 4 (Cntnap4) is a member of the neurexin superfamily of transmembrane molecules that have critical functions in neuronal cell communication. Cntnap4 knockout mice display decreased presynaptic gamma-aminobutyric acid (GABA) and increased dopamine release that is associated with severe, highly penetrant, repetitive, and perseverative movements commonly found in human autism spectrum disorder patients. However, no known function of Cntnap4 has been revealed besides the nervous system. Meanwhile, secretory protein neural EGFL-like 1 (Nell-1) is known to exert potent osteogenic effects in multiple small and large animal models without the off-target effects commonly found with bone morphogenetic protein 2. In this study, while searching for a Nell-1-specific cell surface receptor during osteogenesis, we identified and validated a ligand/receptor-like interaction between Nell-1 and Cntnap4 by demonstrating: 1) Nell-1 and Cntnap4 colocalization on the surface of osteogenic-committed cells; 2) high-affinity interaction between Nell-1 and Cntnap4; 3) abrogation of Nell-1-responsive Wnt and MAPK signaling transduction, as well as osteogenic effects, via Cntnap4 knockdown; and 4) replication of calvarial cleidocranial dysplasiaslike defects observed in Nell-1-deficient mice in Wnt1-Cre-mediated Cntnap4-knockout transgenic mice. In aggregate, these findings indicate that Cntnap4 plays a critical role in Nell-1-responsive osteogenesis. Further, this is the first functional annotation for Cntnap4 in the musculoskeletal system. Intriguingly, Nell-1 and Cntnap4 also colocalize on the surface of human hippocampal interneurons, implicating Nell-1 as a potential novel ligand for Cntnap4 in the nervous system. This unexpected characterization of the ligand/receptor-like interaction between Nell-1 and Cntnap4 indicates a novel biological functional axis for Nell-1 and Cntnap4 in osteogenesis and, potentially, in neural development and function.
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DOI：
10.1098/rstb.1991.0045
发表时间：
1991-05-29
影响因子：
6.3
作者：
CAMPBELL, ID;BARON, M
通讯作者：
BARON, M
DOI：
10.1016/j.bbrc.2015.03.127
发表时间：
2015-05-15
影响因子：
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影响因子：
5.6
作者：
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影响因子：
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作者：
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