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Abstract

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.

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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.

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Acknowledgements

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

Affiliations

  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

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Contributions

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.

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    Supplementary Figures 1–10 and Supplementary Tables 2 and 3

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    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.

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https://doi.org/10.1038/nn.3857

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