收稿日期: 2016-04-19
网络出版日期: 2016-06-30
基金资助
国家自然科学基金重大研究计划资助项目(91539109); 国家自然科学青年基金资助项目(11302129)
Slit-Robo signal pathway in cardiovascular development
Received date: 2016-04-19
Online published: 2016-06-30
近期研究表明, Slit-Robo信号通路对心血管系统的发育和再生发挥了重要功能. Slit3作为促血管新生因子, 能够与其受体Robo4结合, 通过RhoGTPase信号通路调控多个生理和病理过程中的血管新生. Slit3-Robo4信号通路的激活能够促进工程组织中血管网络的形成. 硫酸乙酰肝素通过Slit3-Robo4通路能够调节膈肌发育及其血管新生. Slit-Robo信号通路还参与调控心脏系统静脉回流和心包膜的发育. Slit3的缺失会导致小鼠发育过程中的肾脏缺失和输尿管发育不全. 因此, 进一步研究Slit3-Robo4信号通路对于阐释心血管系统发育和疾病的病因具有重要理论意义, 有望为心血管疾病的预防和治疗提供有力的药物作用靶点, 促进有效药物的开发.
关键词： 发育; 血管新生; Slit3-Robo4信号通路
张冰, 傅怡 . Slit-Robo信号通路在心血管发育中的作用[J]. 上海大学学报(自然科学版), 2016 , 22(3) : 331 -335 . DOI: 10.3969/j.issn.1007-2861.2016.03.009
Slit-Robo pathway has recently been shown to be vital in cardiovascular development and regeneration. Slit3, a proangiogenic factor, regulates angiogenesis and organ formation in embryonic development by binding to its receptor Robo4. Activation of Slit3-Robo4 promotes formation of vascular network in engineered tissues. Heparan sulfate regulates the development of blood vessel and diaphragm through modulating the Slit3-Robo4 signal pathway. Moreover, the Slit-Robo signal pathway plays an essential role in developing cardiac systematic venous return and pericardium. Deficiency of Slit3 leads to developmental defect of other organs such as kidney and ureter. Therefore, further understanding of the Slit3-Robo4 signal pathway in the future may provide a theoretical foundation and therapeutic targets for prevention and therapy of cardiovascular and related diseases.
Key words： angiogenesis; development; Slit3-Robo4 signal pathway
[1] Jürgens G, Wieschaus E, N¨usslein-Volhard C W, et al. Mutations affecting the pattern of the larval cuticle in Drosophila melanogaster. Wilhelm Roux’s archives of developmental
biology [J]. Development Genes & Evolution, 1984, 193(5): 283-295.
[2] Wang K H, 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.
[3] Brose K, Bland K S, Wang K H, et al. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance [J]. Cell, 1999, 96(6): 795-806.
[4] Li H S, Chen J H, Wu W, et al. Vertebrate Slit, a secreted ligand for the transmembrane protein roundabout, is a repellent for olfactory bulb axons [J]. Cell, 1999, 96(6): 807-818.
[5] Kidd T, Bland K S, Goodman C S. Slit is the midline repellent for the Robo receptor in drosophila [J]. Cell, 1999, 96(6): 785-794.
[6] Kramer S G, Kidd T, Simpson J H, et al. Switching repulsion to attraction: changing responses to slit during transition in mesoderm migration [J]. Science, 2001, 292(5517): 737-740.
[7] Hohenester E, Hussain S, Howitt J A. Interaction of the guidance molecule Slit with cellular receptors [J]. Biochemical Society Transactions, 2006, 34(Pt3): 418-421.
[8] Yuan W, Zhou L, Chen J H, et al. The mouse SLIT family: secreted ligands for ROBO expressed in patterns that suggest a role in morphogenesis and axon guidance [J]. Developmental Biology, 1999, 212(2): 290-306.
[9] Liu J, Zhang L, Wang D, et al. Congenital diaphragmatic hernia, kidney agenesis and cardiac defects associated with Slit3-deficiency in mice [J]. Mechanisms of Development, 2003, 120(9): 1059-1070.
[10] Yuan W, Rao Y, Babiuk R P, et al. A genetic model for a central (septum transversum) congenital diaphragmatic hernia in mice lacking Slit3 [J]. Proceedings of the National Academy of Sciences, 2003, 100(14): 8607.
[11] Seeger M, Tear G, Ferres-Marco D, et al. Mutations affecting growth cone guidance in Drosophila: genes necessary for guidance toward or away from the midline [J]. Neuron, 1993, 10(3): 409-426.
[12] Dickinson R E, Duncan W C. The SLIT-ROBO pathway: a regulator of cell function with implications for the reproductive system [J]. Reproduction, 2010, 139(4): 697-704.
[13] Park K W, Morrison C M, Sorensen L K, et al. Robo4 is a vascular-specific receptor that inhibits endothelial migration [J]. Developmental Biology, 2003, 261(1): 251-267.
[14] Dickinson R E, Fegan K S, Ren X, et al. Glucocorticoid regulation of SLIT/ROBO tumour suppressor genes in the ovarian surface epithelium and ovarian cancer cells [J]. PLoS One, 2011, 6(11): e27792.
[15] Zhang B, Dietrich U J G. Repulsive axon guidance molecule Slit3 is a novel angiogenic factor [J]. Blood, 2009, 114(19): 4300-4309.
[16] Carmeliet P. Angiogenesis in life, disease and medicine [J]. Nature, 2006, 438(7070): 932-936.
[17] Jain R K. Molecular regulation of vessel maturation [J]. Nature Medicine, 2003, 9(6): 685-693.
[18] Yancopoulos G D, Davis S, Gale N W, et al. Vascular-specific growth factors and blood vessel formation [J]. Nature, 2000, 407(6801): 242-248.
[19] Carmeliet P, Tessierlavigne M. Common mechanisms of nerve and blood vessel wiring [J]. Nature, 2005, 436(7048): 193-200.
[20] Paul J D, Coulombe K L, Toth P T, et al. SLIT3-ROBO4 activation promotes vascular network formation in human engineered tissue and angiogenesis in vivo [J]. Journal of Molecular and Cellular Cardiology, 2013, 64: 124-131.
[21] Nobuhara K K, Lund D P, Mitchell J, et al. Long-term outlook for survivors of congenital diaphragmatic hernia [J]. Clinics in Perinatology, 1996, 23(4): 873-887.
[22] Zhang B, Xiao W, Qiu H, et al. Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia [J]. The Journal of Clinical Investigation, 2014, 124(1): 209-221.
[23] Mommersteeg M T, AndrewsWD, Ypsilanti A R, et al. Slit-roundabout signaling regulates the development of the cardiac systemic venous return and pericardium [J]. Circulation Research, 2013, 112(3): 465-475.
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