NF1 loss disrupts Schwann cell–axonal interactions: a novel role for semaphorin 4F

  1. Simona Parrinello1,5,
  2. Luke A. Noon1,5,
  3. Marie C. Harrisingh2,
  4. Patrick Wingfield Digby1,
  5. Laura H. Rosenberg1,
  6. Catherine A. Cremona1,
  7. Pedro Echave1,
  8. Adrienne M. Flanagan3,
  9. Luis F. Parada4, and
  10. Alison C. Lloyd1,6
  1. 1 MRC Laboratory for Molecular Cell Biology, Department of Cell and Developmental Biology and the UCL Cancer Institute, University College London, London WC1E 6BT, United Kingdom;
  2. 2 Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut 06520, USA;
  3. 3 Institute of Orthopaedic and Musculoskeletal Science, UCL, Royal National Orthopaedic Hospital, Middlesex HA7 4LP, United Kingdom;
  4. 4 Department of Developmental Biology and Kent Waldrep Foundation Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
  1. 5 These authors contributed equally to this work.

Abstract

Neurofibromatosis type 1 (NF1) patients develop neurofibromas, tumors of Schwann cell origin, as a result of loss of the Ras-GAP neurofibromin. In normal nerves, Schwann cells are found tightly associated with axons, while loss of axonal is a frequent and important early event in neurofibroma development. However, the molecular basis of this physical interaction or how it is disrupted in cancer remains unclear. Here we show that loss of neurofibromin in Schwann cells is sufficient to disrupt Schwann cell/axonal interactions via up-regulation of the Ras/Raf/ERK signaling pathway. Importantly, we identify down-regulation of semaphorin 4F (Sema4F) as the molecular mechanism responsible for the Ras-mediated loss of interactions. In heterotypic cocultures, Sema4F knockdown induced Schwann cell proliferation by relieving axonal -inhibitory signals, providing a mechanism through which loss of axonal contributes to tumorigenesis. Importantly, Sema4F levels were strongly reduced in a panel of human neurofibromas, confirming the relevance of these findings to the human disease. This work identifies a novel role for the guidance-molecules semaphorins in the mediation of Schwann cell/axonal interactions, and provides a molecular mechanism by which heterotypic cell–cell s control cell proliferation and suppress tumorigenesis. Finally, it provides a new approach for the development of therapies for NF1.

Keywords

Footnotes

  • 6 Corresponding author.

    6 E MAIL alison.lloyd{at}ucl.ac.uk; FAX 44-207-679-7805.

  • Supplemental material is available at .

  • Article is online at .

    • Received June 3, 2008.
    • Accepted September 30, 2008.
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