TY - JOUR
T1 - NF1 loss disrupts Schwann cell-axonal interactions
T2 - A novel role for semaphorin 4F
AU - Parrinello, Simona
AU - Noon, Luke A.
AU - Harrisingh, Marie C.
AU - Digby, Patrick Wingfield
AU - Rosenberg, Laura H.
AU - Cremona, Catherine A.
AU - Echave, Pedro
AU - Flanagan, Adrienne M.
AU - Parada, Luis F.
AU - Lloyd, Alison C.
PY - 2008/12/1
Y1 - 2008/12/1
N2 - 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.
AB - 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.
KW - Heterotypic
KW - NF1
KW - Ras
KW - Schwann cell/axonal interactions
KW - Semaphorins
KW - Tumorigenesis
UR - http://www.scopus.com/inward/record.url?scp=57749101397&partnerID=8YFLogxK
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U2 - 10.1101/gad.490608
DO - 10.1101/gad.490608
M3 - Article
C2 - 19056885
AN - SCOPUS:57749101397
SN - 0890-9369
VL - 22
SP - 3335
EP - 3348
JO - Genes and Development
JF - Genes and Development
IS - 23
ER -