This article has been updated


Neuregulin 1 type III is processed following regulated intramembrane proteolysis, which allows communication from the plasma membrane to the nucleus. We found that the intracellular domain of neuregulin 1 type III upregulated the prostaglandin D2 synthase (L-pgds, also known as Ptgds) gene, which, together with the G protein–coupled receptor Gpr44, forms a previously unknown pathway in PNS myelination. Neuronal L-PGDS is secreted and produces the PGD2 prostanoid, a ligand of Gpr44. We found that mice lacking L-PGDS were hypomyelinated. Consistent with this, specific inhibition of L-PGDS activity impaired in vitro myelination and caused myelin damage. Furthermore, in vivo ablation and in vitro knockdown of glial Gpr44 impaired myelination. Finally, we identified Nfatc4, a key transcription factor for myelination, as one of the downstream effectors of PGD2 activity in Schwann cells. Thus, L-PGDS and Gpr44 are previously unknown components of an axo-glial interaction that controls PNS myelination and possibly myelin maintenance.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Change history

  • 17 November 2014

    In the version of this article initially published online, a P value was incorrect on p. 5, first full paragraph. It read “We found similar alterations in 6-month-old sciatic nerves of L-pgds−/− mice, although the difference was not significant (P = 0.649; Supplementary Table 2).” The correct P value is 0.0649. Also, the first Results subheading read “NRG1 type III is cleaved and activates L-PGDS by γ-secretase”; it should have read “NRG1 type III is cleaved by γ-secretase and activates L-PGDS.” The errors have been corrected for the print, PDF and HTML versions of this article.


Primary accessions

Gene Expression Omnibus


  1. 1.

    & Neuregulin-1, a key axonal signal that drives Schwann cell growth and differentiation. Glia 56, 1491–1497 (2008).

  2. 2.

    et al. Control of peripheral nerve myelination by the beta-secretase BACE1. Science 314, 664–666 (2006).

  3. 3.

    et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat. Neurosci. 9, 1520–1525 (2006).

  4. 4.

    et al. TACE (ADAM17) inhibits Schwann cell myelination. Nat. Neurosci. 14, 857–865 (2011).

  5. 5.

    , , & Back signaling by the Nrg-1 intracellular domain. J. Cell Biol. 161, 1133–1141 (2003).

  6. 6.

    et al. Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos. Nat. Neurosci. 7, 1250–1258 (2004).

  7. 7.

    , , & Intramembranous valine linked to schizophrenia is required for neuregulin 1 regulation of the morphological development of cortical neurons. J. Neurosci. 30, 9199–9208 (2010).

  8. 8.

    & Lipocalin-type and hematopoietic prostaglandin D synthases as a novel example of functional convergence. Prostaglandins Other Lipid Mediat. 68–69, 375–382 (2002).

  9. 9.

    , , , & Astrocytes synthesize and secrete prostaglandin D synthetase in vitro. Biochim. Biophys. Acta 1310, 269–276 (1996).

  10. 10.

    et al. Sertoli cell prostaglandin D2 synthetase is a multifunctional molecule: its expression and regulation. Endocrinology 141, 710–721 (2000).

  11. 11.

    et al. De novo synthesis, uptake and proteolytic processing of lipocalin-type prostaglandin D synthase, beta-trace, in the kidneys. FEBS J. 276, 7146–7158 (2009).

  12. 12.

    Genetic insights into the in vivo functions of prostaglandin signaling. Int. J. Biochem. Cell Biol. 45, 1629–1632 (2013).

  13. 13.

    , , , & 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) protects neurons from oxidative death via an Nrf2 astrocyte-specific mechanism independent of PPARgamma. J. Neurochem. 124, 536–547 (2013).

  14. 14.

    , , , & The protective effects of 15-deoxy-delta-(12,14)-prostaglandin J2 in spinal cord injury. Glia 56, 436–448 (2008).

  15. 15.

    & Prostaglandin D synthase: structure and function. Vitam. Horm. 58, 89–120 (2000).

  16. 16.

    & Emerging roles of DP and CRTH2 in allergic inflammation. Trends Mol. Med. 12, 148–158 (2006).

  17. 17.

    et al. Cellular localization of lipocalin-type prostaglandin D synthase (beta-trace) in the central nervous system of the adult rat. J. Comp. Neurol. 428, 62–78 (2000).

  18. 18.

    et al. Calcineurin/NFAT signaling is required for neuregulin-regulated Schwann cell differentiation. Science 323, 651–654 (2009).

  19. 19.

    et al. Determination of guinea-pig cortical gamma-secretase activity ex vivo following the systemic administration of a gamma-secretase inhibitor. Neuropharmacology 48, 1002–1011 (2005).

  20. 20.

    et al. Lipocalin-type prostaglandin D synthase (beta-trace) is located in pigment epithelial cells of rat retina and accumulates within interphotoreceptor matrix. J. Neurosci. 16, 6119–6124 (1996).

  21. 21.

    et al. Prostaglandin D2–mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher. J. Neurosci. 26, 4383–4393 (2006).

  22. 22.

    et al. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J. Lipid Res. 51, 2105–2120 (2010).

  23. 23.

    et al. Biochemical, functional, and pharmacological characterization of AT-56, an orally active and selective inhibitor of lipocalin-type prostaglandin D synthase. J. Biol. Chem. 284, 7623–7630 (2009).

  24. 24.

    , , & Neuronal and glial prostaglandin D synthase isozymes in chick dorsal root ganglia: a light and electron microscopic immunocytochemical study. J. Neurosci. 15, 470–476 (1995).

  25. 25.

    et al. Accelerated glucose intolerance, nephropathy, and atherosclerosis in prostaglandin D2 synthase knock-out mice. J. Biol. Chem. 280, 29946–29955 (2005).

  26. 26.

    et al. Lipocalin-type prostaglandin D synthase produces prostaglandin D2 involved in regulation of physiological sleep. Proc. Natl. Acad. Sci. USA 103, 17949–17954 (2006).

  27. 27.

    et al. Lipocalin-type prostaglandin D synthase/beta-trace is a major amyloid beta-chaperone in human cerebrospinal fluid. Proc. Natl. Acad. Sci. USA 104, 6412–6417 (2007).

  28. 28.

    et al. The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation. Development 136, 1813–1821 (2009).

  29. 29.

    , , & Schwann cell growth factors. Cell 15, 813–822 (1978).

  30. 30.

    , & Protein kinase A–mediated gating of neuregulin-dependent ErbB2-ErbB3 activation underlies the synergistic action of cAMP on Schwann cell proliferation. J. Biol. Chem. 283, 34087–34100 (2008).

  31. 31.

    et al. Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 47, 681–694 (2005).

  32. 32.

    et al. Opposing extracellular signal–regulated kinase and Akt pathways control Schwann cell myelination. J. Neurosci. 24, 6724–6732 (2004).

  33. 33.

    et al. Specific functions for ERK/MAPK signaling during PNS development. Neuron 69, 91–105 (2011).

  34. 34.

    & Regulated intramembrane proteolysis: signaling pathways and biological functions. Physiology (Bethesda) 26, 34–44 (2011).

  35. 35.

    The immunobiology of prostanoid receptor signaling in connecting innate and adaptive immunity. Biomed. Res. Int. 2013, 683405 (2013).

  36. 36.

    et al. Mast cell maturation is driven via a group III phospholipase A2-prostaglandin D2–DP1 receptor paracrine axis. Nat. Immunol. 14, 554–563 (2013).

  37. 37.

    et al. Genome-wide significant locus of beta-trace protein, a novel kidney function biomarker, identified in European and African Americans. Nephrol. Dial. Transplant. 28, 1497–1504 (2013).

  38. 38.

    , , & New insights in the biology of BDNF synthesis and release: implications in CNS function. J. Neurosci. 29, 12764–12767 (2009).

  39. 39.

    et al. Neuronal brain-derived neurotrophic factor is synthesized in excess, with levels regulated by sortilin-mediated trafficking and lysosomal degradation. J. Biol. Chem. 286, 29556–29567 (2011).

  40. 40.

    et al. PGJ(2) provides prolonged CNS stroke protection by reducing white matter edema. PLoS ONE 7, e50021 (2012).

  41. 41.

    et al. Calcineurin-nuclear factor of activated T cells regulation of Krox-20 expression in Schwann cells requires elevation of intracellular cyclic AMP. J. Neurosci. Res. 91, 105–115 (2013).

  42. 42.

    et al. G protein-coupled receptor 30 contributes to improved remyelination after cuprizone-induced demyelination. Glia 61, 420–431 (2013).

  43. 43.

    et al. Decoding signaling and function of the orphan G protein–coupled receptor GPR17 with a small-molecule agonist. Sci. Signal. 6, ra93 (2013).

  44. 44.

    et al. A G protein–coupled receptor is essential for Schwann cells to initiate myelination. Science 325, 1402–1405 (2009).

  45. 45.

    , , , & Gpr126 is essential for peripheral nerve development and myelination in mammals. Development 138, 2673–2680 (2011).

  46. 46.

    & Analysis of Gpr126 function defines distinct mechanisms controlling the initiation and maturation of myelin. Development 140, 3167–3175 (2013).

  47. 47.

    et al. Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation. J. Neurosci. 33, 17976–17985 (2013).

  48. 48.

    et al. ApoD, a glia-derived apolipoprotein, is required for peripheral nerve functional integrity and a timely response to injury. Glia 58, 1320–1334 (2010).

  49. 49.

    et al. ApoE isoform–specific regulation of regeneration in the peripheral nervous system. Hum. Mol. Genet. 20, 2406–2421 (2011).

  50. 50.

    et al. Axonal neuregulin-1 regulates myelin sheath thickness. Science 304, 700–703 (2004).

  51. 51.

    et al. Lack of tactile pain (allodynia) in lipocalin-type prostaglandin D synthase–deficient mice. Proc. Natl. Acad. Sci. USA 96, 726–730 (1999).

  52. 52.

    et al. Essential role for hematopoietic prostaglandin D2 synthase in the control of delayed type hypersensitivity. Proc. Natl. Acad. Sci. USA 103, 5179–5184 (2006).

  53. 53.

    et al. Prostaglandin D2 inhibits wound-induced hair follicle neogenesis through the receptor, Gpr44. J. Invest. Dermatol. 133, 881–889 (2013).

  54. 54.

    et al. Beta 4 integrin and other Schwann cell markers in axonal neuropathy. Glia 17, 294–306 (1996).

  55. 55.

    et al. Dlg1, Sec8 and Mtmr2 regulate membrane homeostasis in Schwann cell myelination. J. Neurosci. 29, 8858–8870 (2009).

  56. 56.

    et al. A minimal human MBP promoter-lacZ transgene is appropriately regulated in developing brain and after optic enucleation, but not in shiverer mutant mice. J. Neurobiol. 34, 10–26 (1998).

  57. 57.

    , , , & Noninvasive assessment of the role of cyclooxygenases in cardiovascular health: a detailed HPLC/MS/MS method. Methods Enzymol. 433, 51–72 (2007).

  58. 58.

    et al. alpha6beta1 and alpha7beta1 integrins are required in Schwann cells to sort axons. J. Neurosci. 33, 17995–18007 (2013).

  59. 59.

    K. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3, 3 (2004).

Download references


We thank V. Marzano and A. Urbani for shotgun mass spectrometry analyses, F. Clarelli for heat map and statistical analyses, G. Fitzgerald (University of Pennsylvania) for providing Gpr44−/− mice, P. Podini for excellent technical assistance with electron microscopy analyses, and P. Del Boccio for LC-MS/MS analyses. We are grateful to M. Buono, S. Previtali and A. Bolino for critical reading of the manuscript and suggestions, and L. Massimino for artwork. Part of this work was carried out in ALEMBIC, an advanced microscopy laboratory at the San Raffaele Scientific Institute. M.G.F. conducted this study in partial fulfillment for her Ph.D. in Molecular and Cellular Neuroscience, San Raffaele University. This study was supported by the Italian Minister of Health (award number GR08-35, C.T.), the European Marie Curie Reintegration Grant (award number IRG 239430-2008, C.T.) and the Agence Nationale pour la Recherche (ANR blanc programme, B.B.B.). C.T. is also supported by Italian Fondazione Italiana Sclerosi Multipla.

Author information


  1. Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.

    • Amelia Trimarco
    • , Maria Grazia Forese
    • , Valentina Alfieri
    • , Alessandra Lucente
    • , Paola Brambilla
    • , Giorgia Dina
    • , Filippo Martinelli Boneschi
    • , Angelo Quattrini
    •  & Carla Taveggia
  2. INSPE at San Raffaele Scientific Institute, Milan, Italy.

    • Amelia Trimarco
    • , Maria Grazia Forese
    • , Valentina Alfieri
    • , Alessandra Lucente
    • , Paola Brambilla
    • , Giorgia Dina
    • , Filippo Martinelli Boneschi
    • , Angelo Quattrini
    •  & Carla Taveggia
  3. Department of Experimental and Clinical Sciences, University “G. D'Annunzio”, Chieti, Italy.

    • Damiana Pieragostino
    •  & Paolo Sacchetta
  4. International Institute for Integrative Sleep medicine, University of Tsukuba, Ibaraki, Japan.

    • Yoshihiro Urade
  5. Institut de Génétique Humaine CNRS UPR1142, Montpellier, France.

    • Brigitte Boizet-Bonhoure


  1. Search for Amelia Trimarco in:

  2. Search for Maria Grazia Forese in:

  3. Search for Valentina Alfieri in:

  4. Search for Alessandra Lucente in:

  5. Search for Paola Brambilla in:

  6. Search for Giorgia Dina in:

  7. Search for Damiana Pieragostino in:

  8. Search for Paolo Sacchetta in:

  9. Search for Yoshihiro Urade in:

  10. Search for Brigitte Boizet-Bonhoure in:

  11. Search for Filippo Martinelli Boneschi in:

  12. Search for Angelo Quattrini in:

  13. Search for Carla Taveggia in:


A.T. designed and conducted the majority of the experiments. M.G.F., V.A. and A.L. contributed to in vitro and biochemical studies. P.B. and F.M.B. performed expression studies. G.D. and A.Q. performed morphological and ultrastructural analyses. Y.U. and B.B.-B. provided transgenic lines and provided input. D.P. and P.S. performed the MS/MS-LC analyses. C.T. designed the experimental plan, supervised the project and wrote the manuscript.

Competing interests

C.T. and A.T. submitted a patent on July 1 2014 (PCT/EP2014/063995) based on the work described in this paper.

Corresponding author

Correspondence to Carla Taveggia.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–10 and Supplementary Tables 2 and 3

  2. 2.

    Supplementary Methods Checklist

Excel files

  1. 1.

    Supplementary Table 1: List of genes upregulated in the Illumina analyses.

    List of genes whose mRNA were upregulated with a FC >2.0 and a P = <0.01 in DRG ICD infected neurons versus not infected, corrected for genes upregulated in EGFP infected neurons. N = 4 different independent RNA preparations and analyses.

About this article

Publication history





Further reading