Research progress on the role of thrombospondin in synapse formation_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

GONG Chaoyang , XIANG Gao , LIU Kaixin ,  ZHANG Haihong

Department of Orthopedics, Gansu Key Laboratory of Osteoarthropathy Research, Lanzhou University Second Hospital, Lanzhou Gansu, 730000, P.R.China;

Corresponding author：

ZHANG Haihong, Email: zhanghaihong1968@sina.com

Keywords：

Thrombospondins; synapse; voltage-dependent calcium channel; neuroligin

DOI：

10.7507/1002-1892.201809006

Video：

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Objective To review the recent progress in the role of thrombospondins (TSPs) in synapse formation in the central nervous system (CNS).Methods A wide range of domestic and foreign literature on the role of TSPs in the synapse formation of the CNS was reviewed. The role of TSPs in structural features, molecules, and related diseases was reviewed.Results As an oligosaccharide protein, TSPs play important roles in angiogenesis, inflammation, osteogenesis, cell proliferation, and apoptosis. In the nervous system, they bind to voltage-dependent calcium channels, neuronectin, and other extracellular matrix proteins and cell surface receptors, and participate in and regulate multiple processes such as synapse formation, maturation, and function in the CNS.Conclusion TSPs as an oligomeric extracellular matrix protein play an important role in the formation of synapses and the repair of synapses after CNS injury.

Citation： GONG Chaoyang, XIANG Gao, LIU Kaixin, ZHANG Haihong. Research progress on the role of thrombospondin in synapse formation. Chinese Journal of Reparative and Reconstructive Surgery, 2019, 33(1): 124-128. doi: 10.7507/1002-1892.201809006 Copy

1.	Mosher DF, Adams JC. Adhesion-modulating/matricellular ECM protein families: a structural, functional and evolutionary appraisal. Matrix Biol, 2012, 31(3): 155-161.
2.	Masli S, Sheibani N, Cursiefen C, et al. Matricellular protein thrombospondins: influence on ocular angiogenesis, wound healing and immuneregulation. Curr Eye Res, 2014, 39(8): 759-774.
3.	Ferrer-Ferrer M, Dityatev A. Shaping synapses by the neural extracellular matrix. Front Neuroanat, 2018, 12: 40.
4.	Risher WC, Eroglu C. Thrombospondins as key regulators of synaptogenesis in the central nervous system. Matrix Biol, 2012, 31(3): 170-177.
5.	Wang B, Guo W, Huang Y. Thrombospondins and synaptogenesis. Neural Regen Res, 2012, 7(22): 1737-1743.
6.	Farhy-Tselnicker I, Allen NJ. Astrocytes, neurons, synapses: a tripartite view on cortical circuit development. Neural Dev, 2018, 13(1): 7.
7.	Torres MD, Garcia O, Tang C, et al. Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome. Free Radic Biol Med, 2018, 114: 10-14.
8.	Chistiakov DA, Melnichenko AA, Myasoedova VA, et al. Thrombospondins: a role in cardiovascular disease. Int J Mol Sci, 2017, 18(7): pii: E1540.
9.	Yan Q, Murphy-Ullrich JE, Song Y. Molecular and structural insight into the role of key residues of thrombospondin-1 and calreticulin in thrombospondin-1-calreticulin binding. Biochemistry, 2011, 50(4): 566-573.
10.	Huang T, Sun L, Yuan X, et al. Thrombospondin-1 is a multifaceted player in tumor progression. Oncotarget, 2017, 8(48): 84546-84558.
11.	Calabro NE, Kristofik NJ, Kyriakides TR. Thrombospondin-2 and extracellular matrix assembly. Biochim Biophys Acta, 2014, 1840(8): 2396-2402.
12.	Risher ML, Sexton HG, Risher WC, et al. Adolescent intermittent alcohol exposure: dysregulation of thrombospondins and synapse formation are associated with decreased neuronal density in the adult hippocampus. Alcohol Clin Exp Res, 2015, 39(12): 2403-2413.
13.	Xu J, Xiao N, Xia J. Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1. Nat Neurosci, 2010, 13(1): 22-24.
14.	Ohnishi H, Kaneko Y, Okazawa H, et al. Differential localization of Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 and CD47 and its molecular mechanisms in cultured hippocampal neurons. J Neurosci, 2005, 25(10): 2702-2711.
15.	Abumrad NA, Ajmal M, Pothakos K, et al. CD36 expression and brain function: does CD36 deficiency impact learning ability? Prostaglandins Other Lipid Mediat, 2005, 77(1-4): 77-83.
16.	Beumer K, Matthies HJ, Bradshaw A, et al. Integrins regulate DLG/FAS2 via a CaM kinase II-dependent pathway to mediate synapse elaboration and stabilization during postembryonic development. Development, 2002, 129(14): 3381-3391.
17.	Herz J, Chen Y. Reelin, lipoprotein receptors and synaptic plasticity. Nat Rev Neurosci, 2006, 7(11): 850-859.
18.	Ehlers MD. Synapse formation: astrocytes spout off. Curr Biol, 2005, 15(4): R134-R137.
19.	Risher WC, Kim N, Koh S, et al. Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. J Cell Biol, 2018, 217(10): 3747-3765.
20.	Christopherson KS, Ullian EM, Stokes CC, et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell, 2005, 120(3): 421-433.
21.	Eroglu C, Allen NJ, Susman MW, et al. Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell, 2009, 139(2): 380-392.
22.	Liu Z, Jiang Y, Li X, et al. Embryonic stem cell-derived peripheral auditory neurons form neural connections with mouse central auditory neurons in vitro via the α2δ1 receptor. Stem Cell Reports, 2018, 11(1): 157-170.
23.	Arikkath J, Campbell KP. Auxiliary subunits: essential components of the voltage-gated calcium channel complex. Curr Opin Neurobiol, 2003, 13(3): 298-307.
24.	Cole RL, Lechner SM, Williams ME, et al. Differential distribution of voltage-gated calcium channel alpha-2 delta (alpha2delta) subunit mRNA-containing cells in the rat central nervous system and the dorsal root ganglia. J Comp Neurol, 2005, 491(3): 246-269.
25.	Davies A, Hendrich J, Van Minh AT, et al. Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends Pharmacol Sci, 2007, 28(5): 220-228.
26.	Liu A, Garg P, Yang S, et al. Epidermal growth factor-like repeats of thrombospondins activate phospholipase Cgamma and increase epithelial cell migration through indirect epidermal growth factor receptor activation. J Biol Chem, 2009, 284(10): 6389-6402.
27.	Crawford DC, Jiang X, Taylor A, et al. Astrocyte-derived thrombospondins mediate the development of hippocampal presynaptic plasticity in vitro. J Neurosci, 2012, 32(38): 13100-13110.
28.	Faria LC, Gu F, Parada I, et al. Epileptiform activity and behavioral arrests in mice overexpressing the calcium channel subunit α2δ-1. Neurobiol Dis, 2017, 102: 70-80.
29.	Maćkowiak M, Mordalska P, Wędzony K. Neuroligins, synapse balance and neuropsychiatric disorders. Pharmacol Rep, 2014, 66(5): 830-835.
30.	Singh SK, Eroglu C. Neuroligins provide molecular links between syndromic and nonsyndromic autism. Sci Signal, 2013, 6(283): re4.
31.	Hoon M, Soykan T, Falkenburger B, et al. Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina. Proc Natl Acad Sci U S A, 2011, 108(7): 3053-3058.
32.	Bemben MA, Shipman SL, Nicoll RA, et al. The cellular and molecular landscape of neuroligins. Trends Neurosci, 2015, 38(8): 496-505.
33.	Kim DH, Lim H, Lee D, et al. Thrombospondin-1 secreted by human umbilical cord blood-derived mesenchymal stem cells rescues neurons from synaptic dysfunction in Alzheimer’s disease model. Sci Rep, 2018, 8(1): 354.
34.	Wittenmayer N, Körber C, Liu H, et al. Postsynaptic Neuroligin1 regulates presynaptic maturation. Proc Natl Acad Sci U S A, 2009, 106(32): 13564-13569.
35.	Bilbo SD, Schwarz JM. Early-life programming of later-life brain and behavior: a critical role for the immune system. Front Behav Neurosci, 2009, 3: 14.
36.	Yamauchi Y, Kuroki M, Imakiire T, et al. Thrombospondin-1 differentially regulates release of IL-6 and IL-10 by human monocytic cell line U937. Biochemical and biophysical research communications, 2002, 290(5): 1551-1557.
37.	Feng Z, Ko CP. Schwann cells promote synaptogenesis at the neuromuscular junction via transforming growth factor-beta1. J Neurosci, 2008, 28(39): 9599-9609.
38.	Packard M, Mathew D, Budnik V. Wnts and TGF beta in synaptogenesis: old friends signalling at new places. Nat Rev Neurosci, 2003, 4(2): 113-120.
39.	Krady MM, Zeng J, Yu J, et al. Thrombospondin-2 modulates extracellular matrix remodeling during physiological angiogenesis. Am J Pathol, 2008, 173(3): 879-891.
40.	Svitkina T, Lin WH, Webb DJ, et al. Regulation of the postsynaptic cytoskeleton: roles in development, plasticity, and disorders. J Neurosci, 2010, 30(45): 14937-14942.
41.	Tashiro A, Yuste R. Regulation of dendritic spine motility and stability by Rac1 and Rho kinase: evidence for two forms of spine motility. Mol Cell Neurosci, 2004, 26(3): 429-440.
42.	Sweetwyne MT, Murphy-Ullrich JE. Thrombospondin1 in tissue repair and fibrosis: TGF-β-dependent and independent mechanisms. Matrix Biol, 2012, 31(3): 178-186.
43.	Zhao Y, Pu D, Sun Y, et al. High glucose-induced defective thrombospondin-1 release from astrocytes via TLR9 activation contributes to the synaptic protein loss. Exp Cell Res, 2018, 363(2): 171-178.
44.	Jayakumar AR, Tong XY, Curtis KM, et al. Decreased astrocytic thrombospondin-1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies. J Neurochem, 2014, 131(3): 333-347.

1. Mosher DF, Adams JC. Adhesion-modulating/matricellular ECM protein families: a structural, functional and evolutionary appraisal. Matrix Biol, 2012, 31(3): 155-161.
2. Masli S, Sheibani N, Cursiefen C, et al. Matricellular protein thrombospondins: influence on ocular angiogenesis, wound healing and immuneregulation. Curr Eye Res, 2014, 39(8): 759-774.
3. Ferrer-Ferrer M, Dityatev A. Shaping synapses by the neural extracellular matrix. Front Neuroanat, 2018, 12: 40.
4. Risher WC, Eroglu C. Thrombospondins as key regulators of synaptogenesis in the central nervous system. Matrix Biol, 2012, 31(3): 170-177.
5. Wang B, Guo W, Huang Y. Thrombospondins and synaptogenesis. Neural Regen Res, 2012, 7(22): 1737-1743.
6. Farhy-Tselnicker I, Allen NJ. Astrocytes, neurons, synapses: a tripartite view on cortical circuit development. Neural Dev, 2018, 13(1): 7.
7. Torres MD, Garcia O, Tang C, et al. Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome. Free Radic Biol Med, 2018, 114: 10-14.
8. Chistiakov DA, Melnichenko AA, Myasoedova VA, et al. Thrombospondins: a role in cardiovascular disease. Int J Mol Sci, 2017, 18(7): pii: E1540.
9. Yan Q, Murphy-Ullrich JE, Song Y. Molecular and structural insight into the role of key residues of thrombospondin-1 and calreticulin in thrombospondin-1-calreticulin binding. Biochemistry, 2011, 50(4): 566-573.
10. Huang T, Sun L, Yuan X, et al. Thrombospondin-1 is a multifaceted player in tumor progression. Oncotarget, 2017, 8(48): 84546-84558.
11. Calabro NE, Kristofik NJ, Kyriakides TR. Thrombospondin-2 and extracellular matrix assembly. Biochim Biophys Acta, 2014, 1840(8): 2396-2402.
12. Risher ML, Sexton HG, Risher WC, et al. Adolescent intermittent alcohol exposure: dysregulation of thrombospondins and synapse formation are associated with decreased neuronal density in the adult hippocampus. Alcohol Clin Exp Res, 2015, 39(12): 2403-2413.
13. Xu J, Xiao N, Xia J. Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1. Nat Neurosci, 2010, 13(1): 22-24.
14. Ohnishi H, Kaneko Y, Okazawa H, et al. Differential localization of Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 and CD47 and its molecular mechanisms in cultured hippocampal neurons. J Neurosci, 2005, 25(10): 2702-2711.
15. Abumrad NA, Ajmal M, Pothakos K, et al. CD36 expression and brain function: does CD36 deficiency impact learning ability? Prostaglandins Other Lipid Mediat, 2005, 77(1-4): 77-83.
16. Beumer K, Matthies HJ, Bradshaw A, et al. Integrins regulate DLG/FAS2 via a CaM kinase II-dependent pathway to mediate synapse elaboration and stabilization during postembryonic development. Development, 2002, 129(14): 3381-3391.
17. Herz J, Chen Y. Reelin, lipoprotein receptors and synaptic plasticity. Nat Rev Neurosci, 2006, 7(11): 850-859.
18. Ehlers MD. Synapse formation: astrocytes spout off. Curr Biol, 2005, 15(4): R134-R137.
19. Risher WC, Kim N, Koh S, et al. Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. J Cell Biol, 2018, 217(10): 3747-3765.
20. Christopherson KS, Ullian EM, Stokes CC, et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell, 2005, 120(3): 421-433.
21. Eroglu C, Allen NJ, Susman MW, et al. Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell, 2009, 139(2): 380-392.
22. Liu Z, Jiang Y, Li X, et al. Embryonic stem cell-derived peripheral auditory neurons form neural connections with mouse central auditory neurons in vitro via the α2δ1 receptor. Stem Cell Reports, 2018, 11(1): 157-170.
23. Arikkath J, Campbell KP. Auxiliary subunits: essential components of the voltage-gated calcium channel complex. Curr Opin Neurobiol, 2003, 13(3): 298-307.
24. Cole RL, Lechner SM, Williams ME, et al. Differential distribution of voltage-gated calcium channel alpha-2 delta (alpha2delta) subunit mRNA-containing cells in the rat central nervous system and the dorsal root ganglia. J Comp Neurol, 2005, 491(3): 246-269.
25. Davies A, Hendrich J, Van Minh AT, et al. Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends Pharmacol Sci, 2007, 28(5): 220-228.
26. Liu A, Garg P, Yang S, et al. Epidermal growth factor-like repeats of thrombospondins activate phospholipase Cgamma and increase epithelial cell migration through indirect epidermal growth factor receptor activation. J Biol Chem, 2009, 284(10): 6389-6402.
27. Crawford DC, Jiang X, Taylor A, et al. Astrocyte-derived thrombospondins mediate the development of hippocampal presynaptic plasticity in vitro. J Neurosci, 2012, 32(38): 13100-13110.
28. Faria LC, Gu F, Parada I, et al. Epileptiform activity and behavioral arrests in mice overexpressing the calcium channel subunit α2δ-1. Neurobiol Dis, 2017, 102: 70-80.
29. Maćkowiak M, Mordalska P, Wędzony K. Neuroligins, synapse balance and neuropsychiatric disorders. Pharmacol Rep, 2014, 66(5): 830-835.
30. Singh SK, Eroglu C. Neuroligins provide molecular links between syndromic and nonsyndromic autism. Sci Signal, 2013, 6(283): re4.
31. Hoon M, Soykan T, Falkenburger B, et al. Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina. Proc Natl Acad Sci U S A, 2011, 108(7): 3053-3058.
32. Bemben MA, Shipman SL, Nicoll RA, et al. The cellular and molecular landscape of neuroligins. Trends Neurosci, 2015, 38(8): 496-505.
33. Kim DH, Lim H, Lee D, et al. Thrombospondin-1 secreted by human umbilical cord blood-derived mesenchymal stem cells rescues neurons from synaptic dysfunction in Alzheimer’s disease model. Sci Rep, 2018, 8(1): 354.
34. Wittenmayer N, Körber C, Liu H, et al. Postsynaptic Neuroligin1 regulates presynaptic maturation. Proc Natl Acad Sci U S A, 2009, 106(32): 13564-13569.
35. Bilbo SD, Schwarz JM. Early-life programming of later-life brain and behavior: a critical role for the immune system. Front Behav Neurosci, 2009, 3: 14.
36. Yamauchi Y, Kuroki M, Imakiire T, et al. Thrombospondin-1 differentially regulates release of IL-6 and IL-10 by human monocytic cell line U937. Biochemical and biophysical research communications, 2002, 290(5): 1551-1557.
37. Feng Z, Ko CP. Schwann cells promote synaptogenesis at the neuromuscular junction via transforming growth factor-beta1. J Neurosci, 2008, 28(39): 9599-9609.
38. Packard M, Mathew D, Budnik V. Wnts and TGF beta in synaptogenesis: old friends signalling at new places. Nat Rev Neurosci, 2003, 4(2): 113-120.
39. Krady MM, Zeng J, Yu J, et al. Thrombospondin-2 modulates extracellular matrix remodeling during physiological angiogenesis. Am J Pathol, 2008, 173(3): 879-891.
40. Svitkina T, Lin WH, Webb DJ, et al. Regulation of the postsynaptic cytoskeleton: roles in development, plasticity, and disorders. J Neurosci, 2010, 30(45): 14937-14942.
41. Tashiro A, Yuste R. Regulation of dendritic spine motility and stability by Rac1 and Rho kinase: evidence for two forms of spine motility. Mol Cell Neurosci, 2004, 26(3): 429-440.
42. Sweetwyne MT, Murphy-Ullrich JE. Thrombospondin1 in tissue repair and fibrosis: TGF-β-dependent and independent mechanisms. Matrix Biol, 2012, 31(3): 178-186.
43. Zhao Y, Pu D, Sun Y, et al. High glucose-induced defective thrombospondin-1 release from astrocytes via TLR9 activation contributes to the synaptic protein loss. Exp Cell Res, 2018, 363(2): 171-178.
44. Jayakumar AR, Tong XY, Curtis KM, et al. Decreased astrocytic thrombospondin-1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies. J Neurochem, 2014, 131(3): 333-347.

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