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Brain Science Advances 2017, 3(4): 237-245 https://doi.org/10.18679/CN11-6030_R.2017.035
Review Article | Open Access | Issue | Published: 01 December 2017

Review of insulin-like growth factor 1 signaling pathway and its role in protection against brain diseases

Show Author's Information Min Wei†,  Lun Dong†,  Hengzhu Zhang( ),  Zhenfei Teng,  Xiaodong Wang,  Zhengcun Yan,  Lei She,  Yuping Li,  Xingdong Wang
Department of Neurosurgery, Northern Jiangsu People’s Hospital, Yangzhou 225001, China

† These authors contributed equally to this paper.

Keywords:
brain, growth factor, IGF-1
Cite this article:
Wei M, Dong L, Zhang H, et al. Review of insulin-like growth factor 1 signaling pathway and its role in protection against brain diseases. Brain Science Advances, 2017, 3(4): 237-245. https://doi.org/10.18679/CN11-6030_R.2017.035
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Abstract Full text About this article

Insulin-like growth factor 1 (IGF-1) is a pluripotent growth factor, with multiple functions in the peripheral and central nervous systems. Increasing evidence suggests that IGF-1 fine-tunes the development of the central nervous system, ensuring proper neuronal differentiation, maturation, and connectivity. It supports neuronal survival and axon growth, and acts on myelinating Schwann cells and oligodendroglia. The biological functions of IGF-1 are modulated by the IGF-1 signaling pathway. Recent studies have proposed the modulation of the members of the IGF-1/IGF-1 signaling pathway as treatment for neuropathologies. In this study, we introduce the structure of IGF-1/2 and its receptors, with the intra-cellular interactions. Further, we review the therapeutic effects of IGF-1 in different models of brain diseases, via activation of different cellular mechanisms.


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About this article

Review of insulin-like growth factor 1 signaling pathway and its role in protection against brain diseases

Show Author's information Min Wei†, Lun Dong†, Hengzhu Zhang( ), Zhenfei Teng, Xiaodong Wang, Zhengcun Yan, Lei She, Yuping Li, Xingdong Wang
Department of Neurosurgery, Northern Jiangsu People’s Hospital, Yangzhou 225001, China

† These authors contributed equally to this paper.

Abstract

Insulin-like growth factor 1 (IGF-1) is a pluripotent growth factor, with multiple functions in the peripheral and central nervous systems. Increasing evidence suggests that IGF-1 fine-tunes the development of the central nervous system, ensuring proper neuronal differentiation, maturation, and connectivity. It supports neuronal survival and axon growth, and acts on myelinating Schwann cells and oligodendroglia. The biological functions of IGF-1 are modulated by the IGF-1 signaling pathway. Recent studies have proposed the modulation of the members of the IGF-1/IGF-1 signaling pathway as treatment for neuropathologies. In this study, we introduce the structure of IGF-1/2 and its receptors, with the intra-cellular interactions. Further, we review the therapeutic effects of IGF-1 in different models of brain diseases, via activation of different cellular mechanisms.

Keywords: brain, growth factor, IGF-1

References(73)

[1]
Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995, 16(1): 3–34.
DOI Google Scholar
[2]
Nishijima T, Piriz J, Duflot S, Fernandez AM, Gaitan G, Gomez-Pinedo U, Verdugo JMG, Leroy F, Soya H, Nuñez A, Torres-Aleman I. Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS. Neuron 2010, 67(5): 834–846.
DOI Google Scholar
[3]
Fernandez AM, Torres-Alemán I. The many faces of insulin-like peptide signalling in the brain. Nat Rev Neurosci 2012, 13(4): 225–239.
DOI Google Scholar
[4]
Annunziata M, Granata R, Ghigo E. The IGF system. Acta Diabetol 2011, 48(1): 1–9.
DOI Google Scholar
[5]
Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 1993, 75(1): 59–72.
DOI Google Scholar
[6]
Baxter RC, Martin JL, Beniac VA. High molecular weight insulin-like growth factor binding protein complex. Purification and properties of the acid-labile subunit from human serum. J Biol Chem 1989, 264(20): 11843–11848.
DOI Google Scholar
[7]
Thomas MJ, Umayahara Y, Shu H, Centrella M, Rotwein P, McCarthy TL. Identification of the cAMP response element that controls transcriptional activation of the insulin-like growth factor-I gene by prostaglandin E2 in osteoblasts. J Biol Chem 1996, 271(36): 21835–21841.
DOI Google Scholar
[8]
Hatey F, Langlois I, Mulsant P, Bonnet A, Benne F, Gasser F. Gonadotropins induce accumulation of insulin-like growth factor I mRNA in pig granulosa cells in vitro. Mol Cell Endocrinol 1992, 86(3): 205–211.
DOI Google Scholar
[9]
Feinstein DL, Heneka MT, Gavrilyuk V, Dello Russo C, Weinberg G, Galea E. Noradrenergic regulation of inflammatory gene expression in brain. Neurochem Int 2002, 41(5): 357–365.
DOI Google Scholar
[10]
Lee SC, Collins M, Vanguri P, Shin ML. Glutamate differentially inhibits the expression of class II MHC antigens on astrocytes and microglia. J Immunol 1992, 148(11): 3391– 3397.
Google Scholar
[11]
Denley A, Cosgrove LJ, Booker GW, Wallace JC, Forbes BE. Molecular interactions of the IGF system. Cytokine Growth Factor Rev 2005, 16(4–5): 421–439.
DOI Google Scholar
[12]
Carson MJ, Behringer RR, Brinster RL, McMorris FA. Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. Neuron 1993, 10(4): 729–740.
DOI Google Scholar
[13]
Ye P, Li LQ, Richards RG, DiAugustine RP, D’Ercole AJ. Myelination is altered in insulin-like growth factor-I null mutant mice. J Neurosci 2002, 22(14): 6041–6051.
DOI Google Scholar
[14]
Camacho-Hubner C, Woods KA, Clark AJ, Savage MO. Insulin-like growth factor (IGF)-I gene deletion. Rev Endocr Metab Disord 2002, 3(4): 357–361.
Google Scholar
[15]
Duan C. Specifying the cellular responses to IGF signals: roles of IGF-binding proteins. J Endocrinol 2002, 175(1): 41–54.
DOI Google Scholar
[16]
Bondy CA, Cheng CM. Signaling by insulin-like growth factor 1 in brain. Eur J Pharmacol 2004, 490(1–3): 25–31.
DOI Google Scholar
[17]
Boisclair YR, Rhoads RP, Ueki I, Wang J, Ooi GT. The acid-labile subunit (ALS) of the 150 kDa IGF-binding protein complex: An important but forgotten component of the circulating IGF system. J Endocrinol 2001, 170(1): 63–70.
DOI Google Scholar
[18]
Hashimoto R, Ono M, Fujiwara H, Higashihashi N, Yoshida M, Enjoh-Kimura T, Sakano K. Binding sites and binding properties of binary and ternary complexes of insulin-like growth factor-II (IGF-II), IGF-binding protein-3, and acid-labile subunit. J Biol Chem 1997, 272(44): 27936–27942.
DOI Google Scholar
[19]
Twigg SM, Baxter RC. Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit. J Biol Chem 1998, 273(11): 6074–6079.
DOI Google Scholar
[20]
Sosa L, Dupraz S, Laurino L, Bollati F, Bisbal M, Cáceres A, Pfenninger KH, Quiroga S. IGF-1 receptor is essential for the establishment of hippocampal neuronal polarity. Nat Neurosci 2006, 9(8): 993–995.
DOI Google Scholar
[21]
Quiroga S, Garofalo RS, Pfenninger KH. Insulin-like growth factor I receptors of fetal brain are enriched in nerve growth cones and contain a beta-subunit variant. Proc Natl Acad Sci USA 1995, 92(10): 4309–4312.
DOI Google Scholar
[22]
Bondy C, Werner H, Roberts CT Jr, LeRoith D. Cellular pattern of type-I insulin-like growth factor receptor gene expression during maturation of the rat brain: comparison with insulin-like growth factors I and II. Neuroscience 1992, 46(4): 909–923.
DOI Google Scholar
[23]
Han VK, D’Ercole AJ, Lund PK. Cellular localization of somatomedin (insulin-like growth factor) messenger RNA in the human fetus. Science 1987, 236(4798): 193–197.
DOI Google Scholar
[24]
Haselbacher GK, Schwab ME, Pasi A, Humbel RE. Insulin-like growth factor II (IGF II) in human brain: regional distribution of IGF II and of higher molecular mass forms. Proc Natl Acad Sci USA 1985, 82(7): 2153–2157.
DOI Google Scholar
[25]
Komoly S, Hudson LD, Webster HD, Bondy CA. Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelination. Proc Natl Acad Sci USA 1992, 89(5): 1894–1898.
DOI Google Scholar
[26]
Lee WH, Clemens JA, Bondy CA. Insulin-like growth factors in the response to cerebral ischemia. Mol Cell Neurosci 1992, 3(1): 36–43.
DOI Google Scholar
[27]
Selvamani A, Sathyan P, Miranda RC, Sohrabji F. An antagomir to microRNA Let7f promotes neuroprotection in an ischemic stroke model. PLoS One 2012, 7(2): e32662.
DOI Google Scholar
[28]
O’Donnell SL, Frederick TJ, Krady JK, Vannucci SJ, Wood TL. IGF-I and microglia/macrophage proliferation in the ischemic mouse brain. Glia 2002, 39(1): 85–97.
DOI Google Scholar
[29]
Rotwein P, Burgess SK, Milbrandt JD, Krause JE. Differential expression of insulin-like growth factor genes in rat central nervous system. Proc Natl Acad Sci USA 1988, 85(1): 265– 269.
DOI Google Scholar
[30]
Kaur C, Sivakumar V, Dheen ST, Ling EA. Insulin-like growth factor I and II expression and modulation in amoeboid microglial cells by lipopolysaccharide and retinoic acid. Neuroscience 2006, 138(4): 1233–1244.
DOI Google Scholar
[31]
Kihira T, Suzuki A, Kubo T, Miwa H, Kondo T. Expression of insulin-like growth factor-II and leukemia inhibitory factor antibody immunostaining on the ionized calcium-binding adaptor molecule 1-positive microglias in the spinal cord of amyotrophic lateral sclerosis patients. Neuropathology 2007, 27(3): 257–268.
DOI Google Scholar
[32]
Hawkes C, Kar S. The insulin-like growth factor-II/ mannose-6-phosphate receptor: structure, distribution and function in the central nervous system. Brain Res Rev 2004, 44(2–3): 117–140.
DOI Google Scholar
[33]
Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I. Serum insulin-like growth factor I regulates brain amyloid-β levels. Nat Med 2002, 8(12): 1390–1397.
DOI Google Scholar
[34]
Russo VC, Gluckman PD, Feldman EL, Werther GA. The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev 2005, 26(7): 916–943.
DOI Google Scholar
[35]
Bilic E, Bilic E, Rudan I, Kusec V, Zurak N, Delimar D, Zagar M. Comparison of the growth hormone, IGF-1 and insulin in cerebrospinal fluid and serum between patients with motor neuron disease and healthy controls. Eur J Neurol 2006, 13(12): 1340–1345.
DOI Google Scholar
[36]
Bellini MJ, Hereñú CB, Goya RG, Garcia-Segura LM. Insulin-like growth factor-I gene delivery to astrocytes reduces their inflammatory response to lipopolysaccharide. J Neuroinflammation 2011, 8: 21.
DOI Google Scholar
[37]
Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, LeRoith D. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci USA 1999, 96(13): 7324–7329.
DOI Google Scholar
[38]
Fernandes de Abreu DA, Caballero A, Fardel P, Stroustrup N, Chen ZN, Lee K, Keyes WD, Nash ZM, López-Moyado IF, Vaggi F, Cornils A, Regenass M, Neagu A, Ostojic I, Liu C, Cho Y, Sifoglu D, Shen Y, Fontana W, Lu H, Csikasz-Nagy A, Murphy CT, Antebi A, Blanc E, Apfeld J, Zhang Y, Alcedo J, Ch’ng Q. An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology. PLoS Genet 2014, 10(3): e1004225.
DOI Google Scholar
[39]
Templeman NM, Murphy CT. Regulation of reproduction and longevity by nutrient-sensing pathways. J Cell Biol 2017, in press, .
DOI Google Scholar
[40]
Bateman JM, McNeill H. Insulin/IGF signalling in neurogenesis. Cell Mol Life Sci 2006, 63(15): 1701–1705.
DOI Google Scholar
[41]
Baltensperger K, Kozma LM, Cherniack AD, Klarlund JK, Chawla A, Banerjee U, Czech MP. Binding of the Ras activator son of sevenless to insulin receptor substrate-1 signaling complexes. Science 1993, 260(5116): 1950–1952.
DOI Google Scholar
[42]
Skolnik EY, Lee CH, Batzer A, Vicentini LM, Zhou M, Daly R, Myers MJ Jr, Backer JM, Ullrich A, White MF. The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling. EMBO J 1993, 12(5): 1929–1936.
DOI Google Scholar
[43]
Cundiff P, Liu LD, Wang YP, Zou JH, Pan YW, Abel G, Duan X, Ming DL, Englund C, Hevner R, Xia ZG. ERK5 MAP kinase regulates neurogenin1 during cortical neurogenesis. PLoS One 2009, 4(4): e5204.
DOI Google Scholar
[44]
Puche JE, Castilla-Cortázar I. Human conditions of insulin-like growth factor-I (IGF-I) deficiency. J Transl Med 2012, 10: 224.
DOI Google Scholar
[45]
Hurtado-Chong A, Yusta-Boyo MJ, Vergaño-Vera E, Bulfone A, de Pablo F, Vicario-Abejón C. IGF-I promotes neuronal migration and positioning in the olfactory bulb and the exit of neuroblasts from the subventricular zone. Eur J Neurosci 2009, 30(5): 742–755.
DOI Google Scholar
[46]
Iwanami A, Cloughesy TF, Mischel PS. Striking the balance between PTEN and PDK1: it all depends on the cell context. Genes Dev 2009, 23: 1699–1704.
DOI Google Scholar
[47]
Onuma TA, Ding YH, Abraham E, Zohar Y, Ando H, Duan CM. Regulation of temporal and spatial organization of newborn GnRH neurons by IGF signaling in zebrafish. J Neurosci 2011, 31(33): 11814–11824.
DOI Google Scholar
[48]
Paliouras GN, Hamilton LK, Aumont A, Joppé SE, Barnabé-Heider F, Fernandes KJL. Mammalian target of rapamycin signaling is a key regulator of the transit-amplifying progenitor pool in the adult and aging forebrain. J Neurosci 2012, 32(43): 15012–15026.
DOI Google Scholar
[49]
Pun RYK, Rolle IJ, LaSarge CL, Hosford BE, Rosen JM, Uhl JD, Schmeltzer SN, Faulkner C, Bronson SL, Murphy BL, Richards DA, Holland KD, Danzer SC. Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron 2012, 75(6): 1022–1034.
DOI Google Scholar
[50]
Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature 2013, 493(7432): 338–345.
DOI Google Scholar
[51]
Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell 2017, 169(2): 361–371.
DOI Google Scholar
[52]
O’Kusky J, Ye P. Neurodevelopmental effects of insulin-like growth factor signaling. Front Neuroendocrinol 2012, 33(3): 230–251.
DOI Google Scholar
[53]
Aksamitiene E, Kiyatkin A, Kholodenko BN. Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. Biochem Soc Trans 2012, 40(1): 139–146.
DOI Google Scholar
[54]
Yang XS, Wei AM, Liu Y, He GL, Zhou Z, Yu ZP. IGF-1 protects retinal ganglion cells from hypoxia-induced apoptosis by activating the Erk-1/2 and Akt pathways. Mol Vis 2013, 19: 1901–1912.
Google Scholar
[55]
Choi H, Lee RH, Bazhanov N, Oh JY, Prockop DJ. Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-κB signaling in resident macrophages. Blood 2011, 118(2): 330–338.
DOI Google Scholar
[56]
Ma J, Guo CY, Guo CW, Sun Y, Liao T, Beattie U, López FJ, Chen DF, Lashkari K. Transplantation of human neural progenitor cells expressing IGF-1 enhances retinal ganglion cell survival. PLoS One 2015, 10(4): e0125695.
DOI Google Scholar
[57]
Hu QC, Lee SY, O’Kusky JR, Ye P. Signalling through the type 1 insulin-like growth factor receptor (IGF1R) interacts with canonical Wnt signalling to promote neural proliferation in developing brain. ASN Neuro 2012, 4(5): e00092.
DOI Google Scholar
[58]
Carron C, Bourdelas A, Li HY, Boucaut JC, Shi DL. Antagonistic interaction between IGF and Wnt/JNK signaling in convergent extension in Xenopus embryo. Mech Dev 2005, 122(11): 1234–1247.
DOI Google Scholar
[59]
Ye P, Hu QC, Liu HD, Yan Y, D’Ercole A J. β-catenin mediates insulin-like growth factor-I actions to promote cyclin D1 mRNA expression, cell proliferation and survival in oligodendroglial cultures. Glia 2010, 58(9): 1031–1041.
DOI Google Scholar
[60]
Carlson SW, Madathil SK, Sama DM, Gao X, Chen JH, Saatman KE. Conditional overexpression of insulin-like growth factor-1 enhances hippocampal neurogenesis and restores immature neuron dendritic processes after traumatic brain injury. J Neuropathol Exp Neurol 2014, 73(8): 734– 746.
DOI Google Scholar
[61]
Diamandis P, Wildenhain J, Clarke ID, Sacher AG, Graham J, Bellows DS, Ling EKM, Ward RJ, Jamieson LG, Tyers M, Dirks PB. Chemical genetics reveals a complex functional ground state of neural stem cells. Nat Chemi Biol 2007, 3(5): 268–273.
DOI Google Scholar
[62]
Laron Z. Somatomedin-1 (recombinant insulin-like growth factor-1): clinical pharmacology and potential treatment of endocrine and metabolic disorders. BioDrugs 1999, 11(1): 55–70.
DOI Google Scholar
[63]
Guler HP, Zapf J, Schmid C, Froesch ER. Insulin-like growth factors I and II in healthy man. Estimations of half-lives and production rates. Acta Endocrinol 1989, 121(6): 753–758.
DOI Google Scholar
[64]
Zhang XH, Zhang L, Cheng X, Guo YX, Sun XH, Chen G, Li HM, Li PC, Lu XH, Tian ML, Qin JB, Zhou H, Jin GH. IGF-1 promotes Brn-4 expression and neuronal differentiation of neural stem cells via the PI3K/Akt pathway. PLoS One 2014, 9(12): e113801.
DOI Google Scholar
[65]
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu SM, Mackey RH, Magid DJ, McGuire DK, Mohler ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB. Heart disease and stroke statistics-2016 update: A report from the american heart association. Circulation 2016, 133(4): e38–e360.
DOI Google Scholar
[66]
Allen BS, Buckberg GD. Studies of isolated global brain ischaemia: I. Overview of irreversible brain injury and evolution of a new concept-redefining the time of brain death. Eur J Cardio-Thorac Surg 2012, 41(5): 1132–1137.
DOI Google Scholar
[67]
Tang XH, Chen F, Lin QM, You Y, Ke J, Zhao S. Bone marrow mesenchymal stem cells repair the hippocampal neurons and increase the expression of IGF-1 after cardiac arrest in rats. Exp Ther Med 2017, 14(5): 4312–4320.
DOI Google Scholar
[68]
Lagina III AT, Calo L, Deogracias M, Sanderson T, Kumar R, Wider J, Sullivan JM. Combination therapy with insulin-like growth factor-1 and hypothermia synergistically improves outcome after transient global brain ischemia in the rat. Acad Emerg Med 2013, 20(4): 344–351.
DOI Google Scholar
[69]
Landel V, Millet P, Baranger K, Loriod B, Féron F. Vitamin D interacts with Esr1 and Igf1 to regulate molecular pathways relevant to Alzheimer’s disease. Mol Neurodegener 2016, 11: 22.
DOI Google Scholar
[70]
Chen WF, Zhou LP, Chen L, Wu L, Gao QG, Wong MS. Involvement of IGF-I receptor and estrogen receptor pathways in the protective effects of ginsenoside Rg1 against Aβ25–35– induced toxicity in PC12 cells. Neurochem Int 2013, 62(8): 1065–1071.
DOI Google Scholar
[71]
Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging 2010, 31(2): 224–243.
DOI Google Scholar
[72]
Hong M, Lee VMY. Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem 1997, 272(31): 19547–19553.
DOI Google Scholar
[73]
Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, Sulkava R, Kivipelto M. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology 2010, 75(13): 1195–1202.
DOI Google Scholar
Publication history
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Publication history

Received: 19 September 2017
Revised: 28 November 2017
Accepted: 05 December 2017
Published: 01 December 2017
Issue date: December 2017

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© The authors 2017.

Acknowledgements

Our work was supported by three funds: 1. 2013 Project of six peak talents in Jiangsu Province, Project number: WSN-022; 2. 2017 Project of Northern Jiangsu People’s Hospital, Project number: yzucms201712; 3. Standard Diagnosis and Treatment Project of scientific technology and social development in Yangzhou. Project number: YZ2015046.

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