NF1 loss disrupts Schwann cell-axonal interactions: A novel role for semaphorin 4F

Simona Parrinello, Luke A. Noon, Marie C. Harrisingh, Patrick Wingfield Digby, Laura H. Rosenberg, Catherine A. Cremona, Pedro Echave, Adrienne M. Flanagan, Luis F. Parada, Alison C. Lloyd

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 contact 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 contact-inhibitory signals, providing a mechanism through which loss of axonal contact 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 contacts control cell proliferation and suppress tumorigenesis. Finally, it provides a new approach for the development of therapies for NF1.

Original languageEnglish (US)
Pages (from-to)3335-3348
Number of pages14
JournalGenes and Development
Volume22
Issue number23
DOIs
StatePublished - Dec 1 2008

Fingerprint

Semaphorins
Neurofibromatosis 1
Schwann Cells
Cell Communication
Neurofibroma
Neurofibromin 1
Carcinogenesis
ras GTPase-Activating Proteins
Cell Proliferation
MAP Kinase Signaling System
Coculture Techniques
Axons
Neoplasms
Up-Regulation
Down-Regulation
Neurons

Keywords

  • Heterotypic
  • NF1
  • Ras
  • Schwann cell/axonal interactions
  • Semaphorins
  • Tumorigenesis

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Parrinello, S., Noon, L. A., Harrisingh, M. C., Digby, P. W., Rosenberg, L. H., Cremona, C. A., ... Lloyd, A. C. (2008). NF1 loss disrupts Schwann cell-axonal interactions: A novel role for semaphorin 4F. Genes and Development, 22(23), 3335-3348. https://doi.org/10.1101/gad.490608

NF1 loss disrupts Schwann cell-axonal interactions : A novel role for semaphorin 4F. / Parrinello, Simona; Noon, Luke A.; Harrisingh, Marie C.; Digby, Patrick Wingfield; Rosenberg, Laura H.; Cremona, Catherine A.; Echave, Pedro; Flanagan, Adrienne M.; Parada, Luis F.; Lloyd, Alison C.

In: Genes and Development, Vol. 22, No. 23, 01.12.2008, p. 3335-3348.

Research output: Contribution to journalArticle

Parrinello, S, Noon, LA, Harrisingh, MC, Digby, PW, Rosenberg, LH, Cremona, CA, Echave, P, Flanagan, AM, Parada, LF & Lloyd, AC 2008, 'NF1 loss disrupts Schwann cell-axonal interactions: A novel role for semaphorin 4F', Genes and Development, vol. 22, no. 23, pp. 3335-3348. https://doi.org/10.1101/gad.490608
Parrinello S, Noon LA, Harrisingh MC, Digby PW, Rosenberg LH, Cremona CA et al. NF1 loss disrupts Schwann cell-axonal interactions: A novel role for semaphorin 4F. Genes and Development. 2008 Dec 1;22(23):3335-3348. https://doi.org/10.1101/gad.490608
Parrinello, Simona ; Noon, Luke A. ; Harrisingh, Marie C. ; Digby, Patrick Wingfield ; Rosenberg, Laura H. ; Cremona, Catherine A. ; Echave, Pedro ; Flanagan, Adrienne M. ; Parada, Luis F. ; Lloyd, Alison C. / NF1 loss disrupts Schwann cell-axonal interactions : A novel role for semaphorin 4F. In: Genes and Development. 2008 ; Vol. 22, No. 23. pp. 3335-3348.
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