Sema3F在神经系统中作用的研究
Study on the Role of Sema3F in the Nervous System
DOI: 10.12677/acm.2025.151019, PDF, HTML, XML,    国家自然科学基金支持
作者: 杨泽睿*, 昝曼杰*, 杨雨佳, 胡可鑫, 张顺禹:内蒙古医科大学第一临床医学院,内蒙古 呼和浩特;杨光路#:内蒙古医科大学附属医院儿科,内蒙古 呼和浩特
关键词: Sema3F神经系统神经发育神经系统疾病Sema3F Nervous System Neurodevelopment Neurological Disorders
摘要: 本文通过综述的形式,论述了保守轴突导向因子Semaphorins的信号蛋白Semaphorins3F (Sema3F)的在神经系统中作用的研究。基于对Sema3F的概述,我们对神经的作用进行了系统总结。在神经发育的过程中,Sema3F作为调节因子,参与皮层椎体神经元树突密度的调节及诱导树突消除和树突细胞体的回缩等多种功能。同样在对Sema3F在感觉神经中的作用的研究中,我们发现其对于嗅觉系统、视觉、内耳和牙神经等有着重要的作用。本文还探讨了Sema3F对于包括自闭症、精神分裂症和癫痫等神经系统疾病的作用。我们认为,Sema3F在神经元的发育、感觉神经以及多种神经系统疾病中均起着重要的作用。
Abstract: This article, in the form of a review, discusses the research on the role of the semaphorin family member Semaphorin 3F (Sema3F), a conserved axon guidance molecule, in the nervous system. Based on an overview of Sema3F, we systematically summarize its effects on neurons. During the process of neural development, Sema3F acts as a regulatory factor, participating in the modulation of dendritic density in cortical pyramidal neurons, as well as inducing dendritic elimination and retraction of dendritic cell bodies, among other functions. Similarly, in studies on the role of Sema3F in sensory neurons, we have found that it plays an important role in the olfactory system, vision, inner ear, and dental nerves. The article also explores the role of Sema3F in various neurological disorders, including autism, schizophrenia, and epilepsy. We believe that Sema3F plays a significant role in the development of neurons, sensory neurons, and a variety of neurological diseases.
文章引用:杨泽睿, 昝曼杰, 杨雨佳, 胡可鑫, 张顺禹, 杨光路. Sema3F在神经系统中作用的研究[J]. 临床医学进展, 2025, 15(1): 121-126. https://doi.org/10.12677/acm.2025.151019

1. Sema3F的概述

Semaphorins是一个庞大的保守轴突导向因子家族,1996年,R. H. Xiang等学者在小细胞肺癌(SCLC)与3号染色体短臂缺失关系研究中,成功分离出一种新型的人类信号蛋白——Sema III/F (HGMW批准符号SEMA3F) [1]。这种蛋白在多种细胞系和组织中表达,其转录本长度为3.8 kb。后续研究中发现,在小鼠发育的第10天即可检测到Sema3F在多种组织中的表达,包括乳腺、肾脏、胎儿脑和肺等,但Sema3F在心脏和肝脏中的表达相对较低[2]

Sema3F在神经系统中有着广泛的作用。

2. Sema3F在神经元中的作用

2.1. Sema3F在神经元发育中的作用

神经细胞粘附分子(neural cell adhesion molecule, NrCAM)是调节皮层锥体神经元树突棘密度的一种新的产后调节因子,可与Sema3F共同作用。这种相互作用通过相同的分子途径,在产后皮层发育阶段促进顶端树突后突触位点的树突回缩[3]。在肌动蛋白水平上,Sema3F启动Rac1和RhoA GTPase的双重信号通路,以促进树突消除[4]。此外,Neurocan是一种存在于周围神经元网中的硫酸软骨素蛋白多糖,它抑制NrCAM/Sema3F诱导的树突消除以及Sema3F诱导的树突和细胞体的回缩[5]

在树突细胞中,Sema3F继续发挥关键作用。多位研究者发现,Sema3F诱导了树突细胞修剪的双信号通路,激活了树突棘中包括Tiam1-Rac1-PAK1-3-LIMK1/2-Cofilin1和RhoA-ROCK1/2-Myosin II在内的多种因子[4]。Sema3F通过nnp-2/neuropilin-2信号轴介导F-肌动蛋白重组,并促进树突细胞的迁移[6]。它还可以诱导齿状颗粒细胞轴突和生长锥的崩溃。然而,在cGMP信号的影响下,它可抑制Sema3F诱导的神经突崩溃[7]

Sema3F及其受体复合物(PlexinA3和Neuropilin-2)作为轴突引导分子,调节轴突生长、导向和靶向海马苔藓纤维。当与轴突中存在的受体复合物结合时,它们作为轴突生长抑制剂,诱导生长锥崩溃[8]。此外,p53通过抑制Sema3F的表达或活性,导致生长锥崩溃,而其过表达则促进生长锥延伸。Sema3F在海马原代神经元中下调p53的表达,导致生长锥崩溃[9]。它还促进了糖原合成酶激酶3 (Glycogen synthase kinase 3, GSK3)的激活,这在成人海马神经发生中发挥作用[10]。突触处AMPA型谷氨酸受体(AMPAR)数量的调节是在稳态缩放过程中控制突触强度以响应神经活动全局变化的主要机制。有研究显示,Sema3F及其受体复合物Npn-2/PlexA3介导皮质神经元的稳态可塑性。Sema3F-Npn-2/PlexA3信号传导对于细胞表面AMPAR稳态降尺度至关重要,以响应神经元活性的增加,Npn-2与AMPAR结合,Sema3F调节这种相互作用。因此,Sema3F-Npn-2/PlexA3信号传导可控制突触发育和突触可塑性[11]

Nrp2/Sema3F信号对于节段性神经嵴迁移至关重要,但对于特定背根神经节的发育并非必需[12]。在对七鳃鳗的研究中发现,Sema3F对于神经嵴衍生的黑素细胞、颅神经节和头骨的模式形成是必不可少的,但对于神经嵴迁移或主干神经嵴衍生物的模式形成并非必需。此外,Nrps和Sema3F在咽部的表达始于神经嵴迁移和咽部的早期定植[13]。此外,研究表明,位于中脑–后脑边界(MHB)的信号中心调节中脑多巴胺能神经元(mDAN)轴突的定向生长,MHB信号中心通过诱导Sema3F调节沿RC轴的mDAN轴突生长极性[14]。但另有研究显示,Sema3F在其受体表达和体感觉皮层和小脑神经的出生后发育中起着相对有限的作用[15]。Sema3F信号还在肌肉特异性脊髓运动池的形成和巩固中发挥了假设功能[16]。此外,Sema3F在建立喙侧前脑、中脑和海马中的边缘系统至关重要,它在边缘流中形成Npn-2 (neuropilin-2)的特异性表达,Sema3F和Npn-2是控制杏仁核回路发育至关重要的第一对引导线索受体[17]。这些发现强调了Sema3F在神经元层面的关键作用,突显了其在神经系统中的关键功能。

2.2. Sema3F在感觉神经中的作用

在感觉神经中,研究者发现Sema3F对于V形嗅觉感觉神经元轴突束化以及这些感觉传入与主嗅觉系统的分离至关重要。然而,它在峰鼻神经元轴突指向前副嗅球(AOB)的过程中仅起次要作用。因此,可以得出结论,Sema3F是主要嗅觉系统中嗅觉感觉轴突层特异性靶向的必要因素[18]。此外,Sema3F与轴突引导受体Npn-2 (neuropilin-2)在鼻器官系统(nos)中以互补方式表达。在形成背–腹轴(D-V)的地形顺序过程中,嗅觉感觉神经元(OSN)轴突的顺序到达以及OSN对Nrp2和Sema3F的渐变和互补表达起到重要作用,这对于建立嗅觉地图地形非常关键[19]

此外,Sema3F是视觉皮层脊髓束(CST)轴突修剪的候选局部线索。它参与启动视觉CST轴突的修剪,并且在视觉CST轴突的下丘脑中表达。视觉CST轴突侧枝的局部靶点对Sema3F的敏感性增加可以启动修剪[20]。并且,膝状神经节轴突在胚胎第13天(E13)到达舌间质,3~4天后穿透真菌状乳头上皮(E17)。Sema3F在这种上皮中表达[21]。在对鸡内耳的研究中,发现Sema3F在其中表达,且Sema3F转录本在E5至E8内耳周围的间质中弱表达。并且在上皮中,Sema3F在E5的嵴和半规管中弱表达。在E6和E8,Sema3F位于嵴两侧微弱表达,表明Sema3F在动物听觉系统中也发挥作用[22]。在牙神经中,Sema3F除了在牙间质基部表达外,还存在于成釉细胞系中。Sema3F可能作为牙靶源性轴突化学排斥剂,控制牙神经供应的建立[23]

2.3. Sema3F在神经系统相关疾病中的作用

Sema3F在自闭症谱系障碍(ASD)中扮演着重要角色。与神经胶质细胞相关的细胞粘附分子NrCAM是一种新发现的脊柱密度负调控因子,它与信号蛋白Sema3F的相互作用与ASD的发病机制有关[24]。另一种因子CRMP2是Sema3F驱动的定型轴突修剪的中介,也是Sema3F依赖的轴突修剪和树突脊柱重塑的关键介质。CRMP2在体内神经回路的形成和完善中具有重要地位。CRMP2的缺乏可能导致与神经发育障碍相关的神经发育缺陷以及其他疾病,如ASD和精神分裂症[25]。Rett综合征(RTT)是另一种自闭症谱系障碍,由转录调节因子甲基CpG结合蛋白2 (MECP2)突变引起。有研究证明,MeCP2缺乏会破坏突触发生前神经连接的建立,并且涉及Sema3F功能的非细胞自主机制可能是Mecp2突变连接建立异常的基础[26]

除了自闭症谱系障碍,Sema3F对其他疾病也有重要影响。在癫痫中,Sema3F的配体及其受体神经纤毛蛋白2 (NPN2)在边缘区内高度表达,NPN2信号传导可能密切指导突触前和突触后位置的并置,促进海马突触功能的发育和成熟。研究发现,NPN2缺陷小鼠的癫痫发作潜伏期较短,癫痫相关死亡的易感性增加,在化学刺激后更容易出现自发性复发性癫痫发作[27]。Sema3F的局部过表达增加了少突胶质细胞前体细胞(Oligodendrocyte progenitor cells, OPC)的募集,从而加速了髓鞘再生的发生。髓鞘再生可以防止脱髓鞘轴突的退化,因此在多发性硬化症(Multiple Sclerosis, MS)患者中促进这一过程可能会阻止神经退行性变,达到治疗效果[28]。此外,Sema3F的缺失还可能导致小鼠运动活动减少,引起焦虑相关行为异常,并增强情境记忆和广泛性恐惧。这证实了Sema3F在神经回路的发展中起着重要作用,这些神经回路是焦虑和恐惧反应某些方面的调节基础[29]。歌舞团综合征是一种常染色体显性发育障碍,与电荷综合征极为相似。它的特点是典型的面部钟塔结合身材矮小,智力残疾,骨骼发现和额外的特征,如心脏和泌尿生殖器畸形,颌裂,听力丧失和眼科异常。歌舞团综合征的主要病因是KMT2基因突变,我们发现Kmt2d能抑制XenopusSema3F表达,而Sema3F的过度表达能部分挽救Kmt2d功能丧失缺陷[30]

3. 总结

综上所述,Sema3F (一种重要的信号分子)与神经系统发育及其相关病理机制之间展现出错综复杂的紧密联系,其重要性日益凸显。尤为显著的是,Npn-2作为Sema3F的关键功能性受体,在介导这一信号转导过程中扮演着不可或缺的角色。

我们已知,Sema3F在神经系统,包括神经元的发育,感觉神经和神经系统疾病中都有着重要的作用。当前研究已揭示,在海马神经元内,Sema3F能够引发CREBBP (CREB结合蛋白)在DNA及RNA层面的表达模式发生显著变化,进而诱导CREB (cAMP响应元件结合蛋白)及其伴侣CREBBP的转录与翻译活动发生时间依赖性的调整,但一个核心问题仍悬而未决:Sema3F是否确切地通过Sema3F/Npn-2信号轴,精细调控CREB的转录与翻译过程,从而实现对海马神经元轴突生长的抑制作用。这一未解之谜的解开,对于我们深入洞悉Sema3F介导的神经疾病发病机制具有重大意义,并将为开发更为精准有效的治疗手段开辟新径。

因此,深入探究Sema3F如何通过其受体Npn-2影响CREB的转录调控网络,不仅是对现有神经生物学理论的丰富与完善,更是向着精准医疗目标迈出的坚实步伐,有望为相关疾病患者带来福音。

基金项目

1. 《癫痫大鼠模型中Sema3F与VEGF相关性研究》,国家自然科学基金项目,项目编号:8226050455;

2. 《蒙药朝伦雄胡-5对难治性癫痫大鼠模型干预作用机制研究》,内蒙古医科大学面上项目,项目编号:YKD2022MS032;

3. 《周细胞调控血脑屏障通透性参与细菌性脑膜炎的机制研究》项目编号:2024SGGZ076;

4. 《原代大鼠海马神经元中Sema3F通过Npn-2受体介导CREBBP改变的研究》,大学生创新创业训练计划国家级创新训练项目,项目编号:202410132006。

NOTES

*共同第一作者。

#通讯作者。

参考文献

[1] Jin, Z., Chau, M.D. and Bao, Z. (2005) Sema3D, Sema3F, and Sema5A Are Expressed in Overlapping and Distinct Patterns in Chick Embryonic Heart. Developmental Dynamics, 235, 163-169.
https://doi.org/10.1002/dvdy.20614
[2] Xiang, R., Hensel, C.H., Garcia, D.K., Carlson, H.C., Kok, K., Daly, M.C., et al. (1996) Isolation of the Human Semaphorin III/F Gene (SEMA3F) at Chromosome 3p21, a Region Deleted in Lung Cancer. Genomics, 32, 39-48.
https://doi.org/10.1006/geno.1996.0074
[3] Demyanenko, G.P., Mohan, V., Zhang, X., Brennaman, L.H., Dharbal, K.E.S., Tran, T.S., et al. (2014) Neural Cell Adhesion Molecule NrCAM Regulates Semaphorin 3F-Induced Dendritic Spine Remodeling. The Journal of Neuroscience, 34, 11274-11287.
https://doi.org/10.1523/jneurosci.1774-14.2014
[4] Duncan, B.W., Mohan, V., Wade, S.D., Truong, Y., Kampov-Polevoi, A., Temple, B.R., et al. (2021) Semaphorin3F Drives Dendritic Spine Pruning through Rho-Gtpase Signaling. Molecular Neurobiology, 58, 3817-3834.
https://doi.org/10.1007/s12035-021-02373-2
[5] Mohan, V., Wyatt, E.V., Gotthard, I., Phend, K.D., Diestel, S., Duncan, B.W., et al. (2018) Neurocan Inhibits Semaphorin 3F Induced Dendritic Spine Remodeling through NrCAM in Cortical Neurons. Frontiers in Cellular Neuroscience, 12, Article 346.
https://doi.org/10.3389/fncel.2018.00346
[6] Curreli, S., Wong, B.S., Latinovic, O., Konstantopoulos, K. and Stamatos, N.M. (2016) Class 3 Semaphorins Induce F-Actin Reorganization in Human Dendritic Cells: Role in Cell Migration. Journal of Leukocyte Biology, 100, 1323-1334.
https://doi.org/10.1189/jlb.2a1114-534r
[7] Yamada, R.X., Matsuki, N. and Ikegaya, Y. (2006) Soluble Guanylyl Cyclase Inhibitor Prevents Sema3F-Induced Collapse of Axonal and Dendritic Growth Cones of Dentate Granule Cells. Biological and Pharmaceutical Bulletin, 29, 796-798.
https://doi.org/10.1248/bpb.29.796
[8] Bertoldi, M.L., Zalosnik, M.I., Fabio, M.C., Aja, S., Roth, G.A., Ronnett, G.V., et al. (2019) Mecp2 Deficiency Disrupts Kainate-Induced Presynaptic Plasticity in the Mossy Fiber Projections in the Hippocampus. Frontiers in Cellular Neuroscience, 13, Article 286.
https://doi.org/10.3389/fncel.2019.00286
[9] Yang, G., Qu, X., Zhang, J., Zhao, W. and Wang, H. (2012) Sema3F Downregulates p53 Expression Leading to Axonal Growth Cone Collapse in Primary Hippocampal Neurons. International Journal of Clinical and Experimental Pathology, 5, 634-641.
[10] Ng, T., Hor, C.H.H., Chew, B., Zhao, J., Zhong, Z., Ryu, J.R., et al. (2016) Neuropilin 2 Signaling Is Involved in Cell Positioning of Adult-Born Neurons through Glycogen Synthase Kinase-3β (GSK3β). Journal of Biological Chemistry, 291, 25088-25095.
https://doi.org/10.1074/jbc.m116.755215
[11] Wang, Q., Chiu, S., Koropouli, E., Hong, I., Mitchell, S., Easwaran, T.P., et al. (2017) Neuropilin-2/plexina3 Receptors Associate with Glua1 and Mediate Sema3f-Dependent Homeostatic Scaling in Cortical Neurons. Neuron, 96, 1084-1098.e7.
https://doi.org/10.1016/j.neuron.2017.10.029
[12] Roffers-Agarwal, J. and Gammill, L.S. (2009) Neuropilin Receptors Guide Distinct Phases of Sensory and Motor Neuronal Segmentation. Development, 136, 1879-1888.
https://doi.org/10.1242/dev.032920
[13] York, J.R., Yuan, T., Lakiza, O. and McCauley, D.W. (2018) An Ancestral Role for Semaphorin3f-Neuropilin Signaling in Patterning Neural Crest within the New Vertebrate Head. Development, 145, Article 164780.
https://doi.org/10.1242/dev.164780
[14] Yamauchi, K., Mizushima, S., Tamada, A., Yamamoto, N., Takashima, S. and Murakami, F. (2009) FGF8 Signaling Regulates Growth of Midbrain Dopaminergic Axons by Inducing Semaphorin3F. The Journal of Neuroscience, 29, 4044-4055.
https://doi.org/10.1523/jneurosci.4794-08.2009
[15] Matsuda, I., Fukaya, M., Nakao, H., Nakao, K., Matsumoto, H., Mori, K., et al. (2010) Development of the Somatosensory Cortex, the Cerebellum, and the Main Olfactory System in Semaphorin3F Knockout Mice. Neuroscience Research, 66, 321-329.
https://doi.org/10.1016/j.neures.2009.12.001
[16] Helmbrecht, M.S., Soellner, H., Castiblanco-Urbina, M.A., Winzeck, S., Sundermeier, J., Theis, F.J., et al. (2015) A Critical Period for Postnatal Adaptive Plasticity in a Model of Motor Axon Miswiring. PLOS ONE, 10, e0123643.
https://doi.org/10.1371/journal.pone.0123643
[17] Sahay, A., Molliver, M.E., Ginty, D.D. and Kolodkin, A.L. (2003) Semaphorin 3F Is Critical for Development of Limbic System Circuitry and Is Required in Neurons for Selective CNS Axon Guidance Events. The Journal of Neuroscience, 23, 6671-6680.
https://doi.org/10.1523/jneurosci.23-17-06671.2003
[18] Cloutier, J., Sahay, A., Chang, E.C., Tessier-Lavigne, M., Dulac, C., Kolodkin, A.L., et al. (2004) Differential Requirements for Semaphorin3F and Slit-1 in Axonal Targeting, Fasciculation, and Segregation of Olfactory Sensory Neuron Projections. The Journal of Neuroscience, 24, 9087-9096.
https://doi.org/10.1523/jneurosci.2786-04.2004
[19] Takeuchi, H., Inokuchi, K., Aoki, M., Suto, F., Tsuboi, A., Matsuda, I., et al. (2010) Sequential Arrival and Graded Secretion of Sema3F by Olfactory Neuron Axons Specify Map Topography at the Bulb. Cell, 141, 1056-1067.
https://doi.org/10.1016/j.cell.2010.04.041
[20] Low, L.K., Liu, X., Faulkner, R.L., Coble, J. and Cheng, H. (2008) Plexin Signaling Selectively Regulates the Stereotyped Pruning of Corticospinal Axons from Visual Cortex. Proceedings of the National Academy of Sciences, 105, 8136-8141.
https://doi.org/10.1073/pnas.0803849105
[21] Vilbig, R., Cosmano, J., Giger, R. and Rochlin, M.W. (2004) Distinct Roles for Sema3a, Sema3f, and an Unidentified Trophic Factor in Controlling the Advance of Geniculate Axons to Gustatory Lingual Epithelium. Journal of Neurocytology, 33, 591-606.
https://doi.org/10.1007/s11068-005-3329-8
[22] Scott, M.K., Yue, J., Biesemeier, D.J., Lee, J.W. and Fekete, D.M. (2019) Expression of Class III Semaphorins and Their Receptors in the Developing Chicken (Gallus Gallus) Inner Ear. Journal of Comparative Neurology, 527, 1196-1209.
https://doi.org/10.1002/cne.24595
[23] Sijaona, A., Luukko, K., Kvinnsland, I.H. and Kettunen, P. (2011) Expression Patterns of Sema3f, Plexina4,-A3, Neuropilin1 and-2 in the Postnatal Mouse Molar Suggest Roles in Tooth Innervation and Organogenesis. Acta Odontologica Scandinavica, 70, 140-148.
https://doi.org/10.3109/00016357.2011.600708
[24] Mohan, V., Sullivan, C.S., Guo, J., Wade, S.D., Majumder, S., Agarwal, A., et al. (2018) Temporal Regulation of Dendritic Spines through Nrcam-Semaphorin3f Receptor Signaling in Developing Cortical Pyramidal Neurons. Cerebral Cortex, 29, 963-977.
https://doi.org/10.1093/cercor/bhy004
[25] Ziak, J., Weissova, R., Jeřábková, K., Janikova, M., Maimon, R., Petrasek, T., et al. (2020) CRMP 2 Mediates Sema3F-dependent Axon Pruning and Dendritic Spine Remodeling. EMBO Reports, 21, e48512.
https://doi.org/10.15252/embr.201948512
[26] Degano, A.L., Pasterkamp, R.J. and Ronnett, G.V. (2009) Mecp2 Deficiency Disrupts Axonal Guidance, Fasciculation, and Targeting by Altering Semaphorin3F Function. Molecular and Cellular Neuroscience, 42, 243-254.
https://doi.org/10.1016/j.mcn.2009.07.009
[27] Gant, J.C., Thibault, O., Blalock, E.M., Yang, J., Bachstetter, A., Kotick, J., et al. (2009) Decreased Number of Interneurons and Increased Seizures in Neuropilin 2 Deficient Mice: Implications for Autism and Epilepsy. Epilepsia, 50, 629-645.
https://doi.org/10.1111/j.1528-1167.2008.01725.x
[28] Aigrot, M., Barthelemy, C., Moyon, S., Dufayet-Chaffaud, G., Izagirre-Urizar, L., Gillet-Legrand, B., et al. (2022) Genetically Modified Macrophages Accelerate Myelin Repair. EMBO Molecular Medicine, 14, e14759.
https://doi.org/10.15252/emmm.202114759
[29] Matsuda, I., Shoji, H., Yamasaki, N., Miyakawa, T. and Aiba, A. (2016) Comprehensive Behavioral Phenotyping of a New Semaphorin 3 F Mutant Mouse. Molecular Brain, 9, Article No. 15.
https://doi.org/10.1186/s13041-016-0196-4
[30] Schwenty-Lara, J., Nehl, D. and Borchers, A. (2019) The Histone Methyltransferase KMT2D, Mutated in Kabuki Syndrome Patients, Is Required for Neural Crest Cell Formation and Migration. Human Molecular Genetics, 29, 305-319.
https://doi.org/10.1093/hmg/ddz284