Skip to main content

Advertisement

Log in

Growth/differentiation factor-15 and its role in peripheral nervous system lesion and regeneration

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

An Erratum to this article was published on 30 July 2015

Abstract

Growth/differentiation factor-15 (GDF-15) is a distant member of the transforming growth factor beta (TGF-β) superfamily. It is widely distributed in the nervous system, where it has been shown to play an important role in neuronal maintenance. The present study investigates the role of endogenous GDF-15 in sciatic nerve (SN) lesions using wild-type (WT) and GDF-15 knock-out (KO) mice. SN of 5–6-month-old mice were crushed or transected. Dorsal root ganglia (DRG) and nerve tissue were analyzed at different time points from 6 h to 9 weeks post-lesion. Both crush and transection induced GDF-15 mRNA and protein in the distal portion of the nerve, with a peak at day 7. DRG neuron death did not significantly differ between the genotypes; similarly, remyelination of regenerating axons was not affected by the genotype. Alternative macrophage activation and macrophage recruitment were more pronounced in the KO nerve. Protrusion speed of axons was similar in the two genotypes but WT axons showed better maturation, as indicated by larger caliber at 9 weeks. Furthermore, the regenerated WT nerve showed better performance in the electromyography test, indicating better functional recovery. We conclude that endogenous GDF-15 is beneficial for axon regeneration following SN crush.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Abe N, Cavalli V (2008) Nerve injury signaling. Curr Opin Neurobiol 18:276–283

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Baek SJ, Horowitz JM, Eling TE (2001) Molecular cloning and characterization of human nonsteroidal anti-inflammatory drug-activated gene promoter. Basal transcription is mediated by Sp1 and Sp3. J Biol Chem 276:33384–33392

    Article  CAS  PubMed  Google Scholar 

  • Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh BJ, Nicholson RC, Fairlie WD, Por SB, Robbins JM, Breit SN (1997) MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A 94:11514–11519

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Charalambous P, Wang X, Thanos S, Schober A, Unsicker K (2013) Regulation and effects of GDF-15 in the retina following optic nerve crush. Cell Tissue Res 353:1–8

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Yu W, Strickland S (2007) Peripheral regeneration. Annu Rev Neurosci 30:209–233

    Article  PubMed  Google Scholar 

  • Cheng JC, Chang HM, Leung PC (2011) Wild-type p53 attenuates cancer cell motility by inducing growth differentiation factor-15 expression. Endocrinology 152:2987–2995

    Article  CAS  PubMed  Google Scholar 

  • Chey S, Claus C, Liebert UG (2011) Improved method for simultaneous isolation of proteins and nucleic acids. Anal Biochem 411:164–166

    Article  CAS  PubMed  Google Scholar 

  • de Jager SC, Bermudez B, Bot I, Koenen RR, Bot M, Kavelaars A, de Waard V, Heijnen CJ, Muriana FJ, Weber C, van Berkel TJ, Kuiper J, Lee SJ, Abia R, Biessen EA (2011) Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J Exp Med 208:217–225

    Article  PubMed Central  PubMed  Google Scholar 

  • Fawcett JW, Keynes RJ (1990) Peripheral nerve regeneration. Annu Rev Neurosci 13:43–60

    Article  CAS  PubMed  Google Scholar 

  • Fenrich K, Gordon T (2004) Canadian Association of Neuroscience review: axonal regeneration in the peripheral and central nervous systems-current issues and advances. Can J Neurol Sci 31:142–156

    PubMed  Google Scholar 

  • Fricker FR, Lago N, Balarajah S, Tsantoulas C, Tanna S, Zhu N, Fageiry SK, Jenkins M, Garratt AN, Birchmeier C, Bennett DL (2011) Axonally derived neuregulin-1 is required for remyelination and regeneration after nerve injury in adulthood. J Neurosci 31:3225–3233

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Giger RJ, Hollis ER, Tuszynski MH (2010) Guidance molecules in axon regeneration. Cold Spring Harb Perspect Biol 2(7):a001867

    Article  PubMed Central  PubMed  Google Scholar 

  • Gold R, Archelos JJ, Hartung HP (1999) Mechanisms of immune regulation in the peripheral nervous system. Brain Pathol (Zur, Switz) 9:343–360

    Article  CAS  Google Scholar 

  • Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32:593–604

    Article  CAS  PubMed  Google Scholar 

  • Gordon T, Gillespie J, Orozco R, Davis L (1991) Axotomy-induced changes in rabbit hindlimb nerves and the effects of chronic electrical stimulation. J Neurosci 11:2157–2169

    CAS  PubMed  Google Scholar 

  • Griffin JW, Thompson WJ (2008) Biology and pathology of nonmyelinating Schwann cells. Glia 56:1518–1531

    Article  PubMed  Google Scholar 

  • Hinoi E, Ochi H, Takarada T, Nakatani E, Iezaki T, Nakajima H, Fujita H, Takahata Y, Hidano S, Kobayashi T, Takeda S, Yoneda Y (2012) Positive regulation of osteoclastic differentiation by growth differentiation factor 15 upregulated in osteocytic cells under hypoxia. J Bone Miner Res 27:938–949

    Article  CAS  PubMed  Google Scholar 

  • Hoffman PN, Cleveland DW, Griffin JW, Landes PW, Cowan NJ, Price DL (1987) Neurofilament gene expression: a major determinant of axonal caliber. Proc Natl Acad Sci U S A 84:3472–3476

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ichikawa T, Suenaga Y, Koda T, Ozaki T, Nakagawara A (2008) TAp63-dependent induction of growth differentiation factor 15 (GDF15) plays a critical role in the regulation of keratinocyte differentiation. Oncogene 27:409–420

    Article  CAS  PubMed  Google Scholar 

  • Johnen H, Lin S, Kuffner T, Brown DA, Tsai VW, Bauskin AR, Wu L, Pankhurst G, Jiang L, Junankar S, Hunter M, Fairlie WD, Lee NJ, Enriquez RF, Baldock PA, Corey E, Apple FS, Murakami MM, Lin EJ, Wang C, During MJ, Sainsbury A, Herzog H, Breit SN (2007) Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat Med 13:1333–1340

    Article  CAS  PubMed  Google Scholar 

  • Kempf T, Zarbock A, Widera C, Butz S, Stadtmann A, Rossaint J, Bolomini-Vittori M, Korf-Klingebiel M, Napp LC, Hansen B, Kanwischer A, Bavendiek U, Beutel G, Hapke M, Sauer MG, Laudanna C, Hogg N, Vestweber D, Wollert KC (2011) GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med 17:581–588

    Article  CAS  PubMed  Google Scholar 

  • Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29:13435–13444

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kluger HM, Hoyt K, Bacchiocchi A, Mayer T, Kirsch J, Kluger Y, Sznol M, Ariyan S, Molinaro A, Halaban R (2011) Plasma markers for identifying patients with metastatic melanoma. Clin Cancer Res 17:2417–2425

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kriz J, Zhu Q, Julien JP, Padjen AL (2000) Electrophysiological properties of axons in mice lacking neurofilament subunit genes: disparity between conduction velocity and axon diameter in absence of NF-H. Brain Res 885:32–44

    Article  CAS  PubMed  Google Scholar 

  • Lajer M, Jorsal A, Tarnow L, Parving HH, Rossing P (2010) Plasma growth differentiation factor-15 independently predicts all-cause and cardiovascular mortality as well as deterioration of kidney function in type 1 diabetic patients with nephropathy. Diabetes Care 33:1567–1572

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Makranz C, Cohen G, Reichert F, Kodama T, Rotshenker S (2006) cAMP cascade (PKA, Epac, adenylyl cyclase, Gi, and phosphodiesterases) regulates myelin phagocytosis mediated by complement receptor-3 and scavenger receptor-AI/II in microglia and macrophages. Glia 53:441–448

    Article  PubMed  Google Scholar 

  • Mensching L, Borger AK, Wang X, Charalambous P, Unsicker K, Haastert-Talini K (2012) Local substitution of GDF-15 improves axonal and sensory recovery after peripheral nerve injury. Cell Tissue Res 350:225–238

    Article  CAS  PubMed  Google Scholar 

  • Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11:723–737

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Navarro X, Viv OM, Valero-Cabr EA (2007) Neural plasticity after peripheral nerve injury and regeneration. Prog Neurobiol 82:163–201

    Article  CAS  PubMed  Google Scholar 

  • Nickel N, Jonigk D, Kempf T, Bockmeyer CL, Maegel L, Rische J, Laenger F, Lehmann U, Sauer C, Greer M, Welte T, Hoeper MM, Golpon HA (2011) GDF-15 is abundantly expressed in plexiform lesions in patients with pulmonary arterial hypertension and affects proliferation and apoptosis of pulmonary endothelial cells. Respir Res 12:62

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457:981–989

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • O’Donnell M, Chance RK, Bashaw GJ (2009) Axon growth and guidance: receptor regulation and signal transduction. Annu Rev Neurosci 32:383–412

    Article  PubMed  Google Scholar 

  • Pannu R, Barbosa E, Singh AK, Singh I (2005) Attenuation of acute inflammatory response by atorvastatin after spinal cord injury in rats. J Neurosci Res 79:340–350

    Article  CAS  PubMed  Google Scholar 

  • Pattichis CS, Schofield I, Merletti R, Parker PA, Middleton LT (1999) Introduction to this special issue. Intelligent data analysis in electromyography and electroneurography. Med Eng Phys 21:379–388

    Article  CAS  PubMed  Google Scholar 

  • Perrin FE, Lacroix S, Aviles-Trigueros M, David S (2005) Involvement of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha and interleukin-1beta in Wallerian degeneration. Brain 128:854–866

    Article  PubMed  Google Scholar 

  • Prinz M, Priller J (2014) Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15:300–312

    Article  CAS  PubMed  Google Scholar 

  • Rohatgi A, Patel P, Das SR, Ayers CR, Khera A, Martinez-Rumayor A, Berry JD, McGuire DK, de Lemos JA (2011) Association of growth differentiation factor-15 with coronary atherosclerosis and mortality in a young, multi-ethnic population: observations from the Dallas heart study. Clin Chem 58:172–182

    Article  PubMed Central  PubMed  Google Scholar 

  • Saijilafu, Hur EM, Zhou FQ (2011) Genetic dissection of axon regeneration via in vivo electroporation of adult mouse sensory neurons. Nat Commun 2:543

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schindowski K, von Bohlen und Halbach O, Strelau J, Ridder DA, Herrmann O, Schober A, Schwaninger M, Unsicker K (2011) Regulation of GDF-15, a distant TGF-beta superfamily member, in a mouse model of cerebral ischemia. Cell Tissue Res 343:399–409

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schlittenhardt D, Schober A, Strelau J, Bonaterra GA, Schmiedt W, Unsicker K, Metz J, Kinscherf R (2004) Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions. Cell Tissue Res 318:325–333

    Article  CAS  PubMed  Google Scholar 

  • Schober A, Bottner M, Strelau J, Kinscherf R, Bonaterra GA, Barth M, Schilling L, Fairlie WD, Breit SN, Unsicker K (2001) Expression of growth differentiation factor-15/ macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in the perinatal, adult, and injured rat brain. J Comp Neurol 439:32–45

    Article  CAS  PubMed  Google Scholar 

  • Simons M, Trotter J (2007) Wrapping it up: the cell biology of myelination. Curr Opin Neurobiol 17:533–540

    Article  CAS  PubMed  Google Scholar 

  • Stassart RM, Fledrich R, Velanac V, Brinkmann BG, Schwab MH, Meijer D, Sereda MW, Nave KA (2013) A role for Schwann cell-derived neuregulin-1 in remyelination. Nat Neurosci 16:48–54

    Article  CAS  PubMed  Google Scholar 

  • Stoll G, Müller HW (1999) Nerve injury, axonal degeneration and neural regeneration: basic insights. Brain Pathol 9:313–325

    Article  CAS  PubMed  Google Scholar 

  • Strelau J, Sullivan A, Bottner M, Lingor P, Falkenstein E, Suter-Crazzolara C, Galter D, Jaszai J, Krieglstein K, Unsicker K (2000) Growth/differentiation factor-15/macrophage inhibitory cytokine-1 is a novel trophic factor for midbrain dopaminergic neurons in vivo. J Neurosci 20:8597–8603

    CAS  PubMed  Google Scholar 

  • Strelau J, Schmeer C, Peterziel H, Sackmann T, Herold-Mende C, Steiner H, Weller M, Unsicker K (2008) Expression and putative functions of GDF-15, a member of the TGF-beta superfamily, in human glioma and glioblastoma cell lines. Cancer Lett 270:30–39

    Article  CAS  PubMed  Google Scholar 

  • Strelau J, Strzelczyk A, Rusu P, Bendner G, Wiese S, Diella F, Altick AL, von Bartheld CS, Klein R, Sendtner M, Unsicker K (2009) Progressive postnatal motoneuron loss in mice lacking GDF-15. J Neurosci 29:13640–13648

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tetzlaff W, Leonard C, Krekoski CA, Parhad IM, Bisby MA (1996) Reductions in motoneuronal neurofilament synthesis by successive axotomies: a possible explanation for the conditioning lesion effect on axon regeneration. Exp Neurol 139:95–106

    Article  CAS  PubMed  Google Scholar 

  • Tofaris GK, Patterson PH, Jessen KR, Mirsky R (2002) Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J Neurosci 22:6696–6703

    CAS  PubMed  Google Scholar 

  • Unsicker K, Spittau B, Krieglstein K (2013) The multiple facets of the TGF-β family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1. Cytokine Growth Factor Rev 24:373–384

    Article  CAS  PubMed  Google Scholar 

  • Vanhara P, Lincova E, Kozubik A, Jurdic P, Soucek K, Smarda J (2009) Growth/differentiation factor-15 inhibits differentiation into osteoclasts–a novel factor involved in control of osteoclast differentiation. Differentiation 78:213–222

    Article  CAS  PubMed  Google Scholar 

  • Waxman SG (1980) Determinants of conduction velocity in myelinated nerve fibers. Muscle Nerve 3:141–150

    Article  CAS  PubMed  Google Scholar 

  • Yang H, Park SH, Choi HJ, Moon Y (2010) The integrated stress response-associated signals modulates intestinal tumor cell growth by NSAID-activated gene 1 (NAG-1/MIC-1/PTGF-beta). Carcinogenesis 31:703–711

    Article  CAS  PubMed  Google Scholar 

  • Ydens E, Cauwels A, Asselbergh B, Goethals S, Peeraer L, Lornet G, Almeida-Souza L, Van Ginderachter JA, Timmerman V, Janssens S (2012) Acute injury in the peripheral nervous system triggers an alternative macrophage response. J Neuroinflammation 9:176

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Prof. Dr. Irmgard Merfort, Dr. Attila Magyar, Dr. Veronica La Padula and Dr. Björn Spittau for the scientific discussions. We would like to thank Sigrun Nestel and Barbara Joch for their help with electron microscopy. We also thank André Heinen and Patrick Küry for the introduction to Labchart software and the use of the recording and stimulation equipment PowerLab26T for EMG measurements. XW was financially supported by the China Scholarship Council (CSC). JK was supported by a fellowship through the DFG Research Training Group 1033.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Klaus Unsicker.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, X., Krebbers, J., Charalambous, P. et al. Growth/differentiation factor-15 and its role in peripheral nervous system lesion and regeneration. Cell Tissue Res 362, 317–330 (2015). https://doi.org/10.1007/s00441-015-2219-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-015-2219-3

Keywords

Navigation