Int J Stomatol ›› 2019, Vol. 46 ›› Issue (6): 680-686.doi: 10.7518/gjkq.2019091

• Reviews • Previous Articles     Next Articles

Axon guidance molecules and their role in oral tissue regeneration

Sun Zhaoze1,2,3,Liu Shuang2,3,Li Shu1,2,3()   

  1. 1. Dept. of Periodontology, School and Hospital of Stomatology, Shandong University, Jinan 250012, China
    2. Shandong Key Laboratory of Oral Tissue Regeneration, Jinan 250012, China
    3. Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan 250012, China
  • Received:2019-04-19 Revised:2019-08-09 Online:2019-11-01 Published:2019-11-14
  • Contact: Shu Li
  • Supported by:
    This study was supported by Shandong Natural Science Foundation(ZR2019MH006)


During the development of the nervous system, axon guidance molecules guide the axons to grow along a particular path in a very precise manner. With increasing research on axon guidance molecules and their receptors, results have demonstrated that axon guidance molecules do not only guide axon growth but also participate in angiogenesis, bone regeneration and the development and regeneration of oral tissues through various signalling pathways. Such work provides new ideas for the study and development of treatments for oral diseases. This article reviews the related roles of the four major axon guidance molecules (Slits, Semaphorins, Netrins and Ephrins) in tissue regeneration and oral tissue regeneration.

Key words: axon guidance molecule, tissue regeneration, oral tissue regeneration

CLC Number: 

  • Q136

[1] Kolodkin AL, Tessier-Lavigne M . Mechanisms and molecules of neuronal wiring: a primer[J]. Cold Spring Harb Perspect Biol, 2011,3(6). doi: 10.1101/cshperspect.a001727.
[2] Dickson BJ, Senti KA . Axon guidance: growth cones make an unexpected turn[J]. Curr Biol, 2002,12(6):R218-R220.
[3] Tessier-Lavigne M, Goodman CS . The molecular biology of axon guidance[J]. Science, 1996,274(5290):1123-1133.
[4] Suter DM, Forscher P . An emerging link between cytoskeletal dynamics and cell adhesion molecules in growth cone guidance[J]. Curr Opin Neurobiol, 1998,8(1):106-116.
[5] Xu XY, Li X, Wang J , et al. Concise review: perio-dontal tissue regeneration using stem cells: strategies and translational considerations[J]. Stem Cells Transl Med, 2019,8(4):392-403.
[6] Wang KH, Brose K, Arnott D , et al. Biochemical purification of a mammalian slit protein as a positive regulator of sensory axon elongation and branching[J]. Cell, 1999,96(6):771-784.
[7] Wong K, Park HT, Wu JY , et al. Slit proteins: mo-lecular guidance cues for cells ranging from neurons to leukocytes[J]. Curr Opin Genet Dev, 2002,12(5):583-591.
[8] Alto LT, Terman JR . Semaphorins and their signaling mechanisms[J]. Methods Mol Biol, 2017,1493:1-25.
[9] Jongbloets BC, Pasterkamp RJ . Semaphorin signal-ling during development[J]. Development, 2014,141(17):3292-3297.
[10] Garrett AM, Jucius TJ, Sigaud LP , et al. Analysis of expression pattern and genetic deletion of Netrin5 in the developing mouse[J]. Front Mol Neurosci, 2016,9:3.
[11] Cirulli V, Yebra M . Netrins: beyond the brain[J]. Nat Rev Mol Cell Biol, 2007,8(4):296-306.
[12] Lai KO, Ip NY . Synapse development and plasticity: roles of ephrin/Eph receptor signaling[J]. Curr Opin Neurobiol, 2009,19(3):275-283.
[13] Xi HQ, Wu XS, Wei B , et al. Eph receptors and eph-rins as targets for cancer therapy[J]. J Cell Mol Med, 2012,16(12):2894-2909.
[14] Brose K, Tessier-Lavigne M . Slit proteins: key regu-lators of axon guidance, axonal branching, and cell migration[J]. Curr Opin Neurobiol, 2000,10(1):95-102.
[15] Song H, Ming G, He Z , et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides[J]. Science, 1998,281(5382):1515-1518.
[16] Winberg ML, Mitchell KJ, Goodman CS . Genetic analysis of the mechanisms controlling target selection: complementary and combinatorial functions of ne-trins, semaphorins, and IgCAMs[J]. Cell, 1998,93(4):581-591.
[17] Bashaw GJ, Goodman CS . Chimeric axon guidance receptors: the cytoplasmic domains of slit and netrin receptors specify attraction versus repulsion[J]. Cell, 1999,97(7):917-926.
[18] Cowan CW, Shao YR, Sahin M , et al. Vav family GEFs link activated Ephs to endocytosis and axon guidance[J]. Neuron, 2005,46(2):205-217.
[19] Sadri-Ardekani H, Atala A . Regenerative medicine[J]. Methods, 2016,99:1-2.
[20] Carmeliet P . Angiogenesis in life, disease and me-dicine[J]. Nature, 2005,438(7070):932-936.
[21] Blockus H, Chédotal A . Slit-Robo signaling[J]. Development, 2016,143(17):3037-3044.
[22] Li S, Huang L, Sun Y , et al. Slit2 promotes angio-genic activity via the Robo1-VEGFR2-ERK1/2 pathway in both in vivo and in vitro studies[J]. Invest Ophthalmol Vis Sci, 2015,56(9):5210-5217.
[23] Wu MF, Liao CY, Wang LY , et al. The role of Slit-Robo signaling in the regulation of tissue barriers[J]. Tissue Barriers, 2017,5(2):e1331155.
[24] Rama N, Dubrac A, Mathivet T , et al. Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization[J]. Nat Med, 2015,21(5):483-491.
[25] Kim J, Oh WJ, Gaiano N , et al. Semaphorin 3E- Plexin-D1 signaling regulates VEGF function in developmental angiogenesis via a feedback mecha-nism[J]. Genes Dev, 2011,25(13):1399-1411.
[26] Basile JR, Barac A, Zhu T , et al. Class Ⅳ sema-phorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B[J]. Cancer Res, 2004,64(15):5212-5224.
[27] Hu S, Liu Y, You T , et al. Semaphorin 7A promotes VEGFA/VEGFR2-mediated angiogenesis and intra-plaque neovascularization in ApoE -/- mice [J]. Front Physiol, 2018,9:1718.
[28] Yang X, Li S, Zhong J , et al. CD151 mediates netrin-1-induced angiogenesis through the Src-FAK-Paxil-lin pathway[J]. J Cell Mol Med, 2017,21(1):72-80.
[29] Lejmi E, Leconte L, Pédron-Mazoyer S , et al. Netrin- 4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B[J]. Proc Natl Acad Sci USA, 2008,105(34):12491-12496.
[30] Yang D, Jin C, Ma H , et al. EphrinB2/EphB4 path-way in postnatal angiogenesis: a potential therapeutic target for ischemic cardiovascular disease[J]. Angio-genesis, 2016,19(3):297-309.
[31] Matsuo K, Irie N . Osteoclast-osteoblast communication[J]. Arch Biochem Biophys, 2008,473(2):201-209.
[32] Kim BJ, Lee YS, Lee SY , et al. Osteoclast-secreted SLIT3 coordinates bone resorption and formation[J]. J Clin Invest, 2018,128(4):1429-1441.
[33] Hayashi M, Nakashima T, Taniguchi M , et al. Osteo-protection by semaphorin 3A[J]. Nature, 2012,485(7396):69-74.
[34] Liu L, Wang J, Song X , et al. Semaphorin 3A pro-motes osteogenic differentiation in human alveolar bone marrow mesenchymal stem cells[J]. Exp Ther Med, 2018,15(4):3489-3494.
[35] Maruyama K, Kawasaki T, Hamaguchi M , et al. Bone-protective functions of Netrin 1 protein[J]. J Biol Chem, 2016,291(46):23854-23868.
[36] Irie N, Takada Y, Watanabe Y , et al. Bidirectional signaling through ephrinA2-EphA2 enhances clastogenesis and suppresses osteoblastogenesis[J]. J Biol Chem, 2009,284(21):14637-14644.
[37] Kalkan R, Tulay P . The interactions between bone remodelling, estrogen hormone and EPH family genes[J]. Crit Rev Eukaryot Gene Expr, 2018,28(2):135-138.
[38] 王丽美 . ephrinB2-EphB4正向信号介导的TNF-α调控成骨细胞分化过程中的作用研究[D]. 济南: 山东大学, 2017.
Wang LM . Effects of ephrinB2-EphB4 forward signaling on TNF-α-regulated osteoblastic differenti-ation[D]. Jinan: Shandong University, 2017.
[39] Shin JE, Cho Y . Epigenetic regulation of Axon re-generation after neural injury[J]. Mol Cells, 2017,40(1):10-16.
[40] Abe N, Cavalli V . Nerve injury signaling[J]. Curr Opin Neurobiol, 2008,18(3):276-283.
[41] 田乐 . 睫状神经营养因子CNTF和轴突导向因子Slit2在糖尿病角膜病变中的作用及分子机制研究[D]. 青岛: 青岛大学, 2015.
Tian L . Role and molecular mechanism of ciliary neurotrophic factor CNTF and axon guidance factor Slit2 in diabetic keratopathy[D]. Qingdao: Qingdao University, 2015.
[42] Zhang M, Zhou Q, Luo Y , et al. Semaphorin3A induces nerve regeneration in the adult cornea—a switch from its repulsive role in development[J]. PLoS One, 2018,13(1):e0191962.
[43] Lv J, Sun X, Ma J , et al. Netrin-1 induces the migration of Schwann cells via p38 MAPK and PI3K-Akt signaling pathway mediated by the UNC5B receptor[J]. Biochem Biophys Res Commun, 2015,464(1):263-268.
[44] Afshari FT, Kwok JC, Fawcett JW . Astrocyte-pro-duced ephrins inhibit schwann cell migration via VAV2 signaling[J]. J Neurosci, 2010,30(12):4246-4255.
[45] Fredman G, Oh SF, Ayilavarapu S , et al. Impaired phagocytosis in localized aggressive periodontitis: rescue by Resolvin E1[J]. PLoS One, 2011,6(9):e24422.
[46] Zhao Y, Su Y, Ye L . Slit-Robo: a potential way to treat periodontitis[J]. Med Hypotheses, 2012,79(2):186-188.
[47] Wada N, Maeda H, Hasegawa D , et al. Semaphorin 3A induces mesenchymal-stem-like properties in human periodontal ligament cells[J]. Stem Cells Dev, 2014,23(18):2225-2236.
[48] Liu L, Wang J, Song X , et al. Semaphorin 3A pro-motes osteogenic differentiation in human alveolar bone marrow mesenchymal stem cells[J]. Exp Ther Med, 2018,15(4):3489-3494.
[49] Zhu SY, Wang PL, Liao CS , et al. Transgenic ex-pression of ephrinB2 in periodontal ligament stem cells (PDLSCs) modulates osteogenic differentiation via signaling crosstalk between ephrinB2 and EphB4 in PDLSCs and between PDLSCs and pre-osteo-blasts within co-culture[J]. J Periodontal Res, 2017,52(3):562-573.
[50] Heng BC, Wang S, Gong T , et al. EphrinB2 signaling enhances osteogenic/odontogenic differentiation of human dental pulp stem cells[J]. Arch Oral Biol, 2018,87:62-71.
[51] Li M, Zhang C, Jin L , et al. Porphyromonas gin-givalis lipopolysaccharide regulates ephrin/Eph signalling in human periodontal ligament fibroblasts[J]. J Periodontal Res, 2017,52(5):913-921.
[52] Yoshida S, Wada N, Hasegawa D , et al. Semaphorin 3A induces odontoblastic phenotype in dental pulp stem cells[J]. J Dent Res, 2016,95(11):1282-1290.
[53] Matsumura S, Quispe-Salcedo A, Schiller CM , et al. IGF-1 mediates EphrinB1 activation in regulating tertiary dentin formation[J]. J Dent Res, 2017,96(10):1153-1161.
[54] Cao Y, Song M, Kim E , et al. Pulp-dentin regenera-tion: current state and future prospects[J]. J Dent Res, 2015,94(11):1544-1551.
[55] Stokowski A, Shi S, Sun T , et al. EphB/ephrin-B in- teraction mediates adult stem cell attachment, sprea-ding, and migration: implications for dental tissue repair[J]. Stem Cells, 2007,25(1):156-164.
[1] Wang Jiaxi,Mingyue Lü,Yuan Quan. Research progress on sticky bone in oral tissue regeneration [J]. Int J Stomatol, 2023, 50(5): 594-602.
[2] Fan Lin,Sun Jiang.. Application of microneedles in stomatology [J]. Int J Stomatol, 2023, 50(4): 472-478.
[3] Man Yi, Huang Dingming. Combined treatment strategy of oral implantology and endodontics microsurgery: clinical protocol and practical cases (part 2) [J]. Int J Stomatol, 2022, 49(6): 621-632.
[4] Man Yi, Huang Dingming. Combined treatment strategy of oral implantology and endodontic microsurgery for bone augmentation and en-dodontic diseases in aesthetic area (part 1): application basis and indications [J]. Int J Stomatol, 2022, 49(5): 497-505.
[5] Li Pei,Lin Ling,Zhao Wei.. Research progress on the stem cells from human exfoliated deciduous teeth in the regeneration and repair of oral tissue [J]. Int J Stomatol, 2022, 49(4): 483-488.
[6] Zhao Wenjun,Chen Yu. Research progress on periodontal functional gradient membrane for guided tissue/bone regeneration [J]. Int J Stomatol, 2021, 48(4): 391-397.
[7] Wang Shiqi,Chang Yaqin,Chen Bin,Tan Baochun,Ni Yanhong. Comparison of clinical outcomes between using bone graft alone and the combination of bone graft with membrane for periodontal regeneration therapy: a systematic review and Meta-analysis [J]. Int J Stomatol, 2020, 47(6): 644-651.
[8] Tingting Jia,Shiguo Yan. Research progress on the role of special AT-rich sequence binding protein 2 in maxillofacial development and perio-dontal regeneration [J]. Int J Stomatol, 2019, 46(3): 320-325.
[9] Zhengmou Dong,Rui Liu,Luchuan Liu,Xiujie Wen. Research progress on the seed cells in periodontal tissue regeneration [J]. Inter J Stomatol, 2019, 46(1): 48-54.
[10] Jiangxue Tian,Longyi Mo,Xiaoyue Jia,Chengcheng Liu,Xin. Xu. Role of transforming growth factor-β in periodontitis [J]. Inter J Stomatol, 2018, 45(5): 553-559.
[11] Lin Yunfeng, Li Songhang. Research progress on application of DNA origami in stem cell field [J]. Inter J Stomatol, 2018, 45(3): 249-254.
[12] Liu Zhenzhen, Fang Jiao, Zhao Jinghui, Zou Jingting, Xiang Xingchen, Wang Jia, Zhou Yanmin. A review on recent developments in pluripotency of gingiva-derived mesenchymal stem cells [J]. Inter J Stomatol, 2018, 45(1): 55-58.
[13] Guan Wei, Wang Changning.. Application of acellular dermal matrix in periodontology [J]. Inter J Stomatol, 2017, 44(6): 669-673.
[14] Gu Nan, Sun Xin, Liu Fuping, Zhang Yuna, Zhang Xue, Li Haiying.. Biological characteristics of stem cells from human-exfoliated deciduous teeth [J]. Int J Stomatol, 2015, 42(6): 715-719.
[15] Li Xinyi, Dong Wei. Enamel matrix protein in enhancing periodontal tissue regeneration [J]. Inter J Stomatol, 2015, 42(5): 600-605.
Full text



[1] . [J]. Foreign Med Sci: Stomatol, 1999, 26(06): .
[2] . [J]. Foreign Med Sci: Stomatol, 1999, 26(06): .
[3] . [J]. Foreign Med Sci: Stomatol, 1999, 26(06): .
[4] . [J]. Foreign Med Sci: Stomatol, 1999, 26(06): .
[5] . [J]. Foreign Med Sci: Stomatol, 1999, 26(06): .
[6] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[7] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[8] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[9] . [J]. Foreign Med Sci: Stomatol, 1999, 26(04): .
[10] . [J]. Foreign Med Sci: Stomatol, 1999, 26(04): .