Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells.
The NF1 tumor suppressor gene encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras signaling. Mutations in NF1 cause neurofibromatosis type 1 (NF1). The development of neurofibromas, which are complex tumors composed of multiple cell types, is a hallmark of NF1. Somatic inactivation of murine Nf1 in Schwann cells is necessary, but not sufficient, to initiate neurofibroma formation. Neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1+/-) microenvironment. Mast cells infiltrate neurofibromas, where they secrete proteins that can remodel the ECM and initiate angiogenesis. Thus, identification of mechanisms responsible for mast cell migration to tumor microenvironments is important for understanding tumorigenesis and for designing potential therapies. Here, we show that homozygous Nf1 mutant (Nf1-/-) Schwann cells secrete Kit ligand (KitL), which stimulates mast cell migration, and that Nf1+/- mast cells are hypermotile in response to KitL. Furthermore, we link hyperactivation of the Ras-class IA-PI3K-Rac2 pathway to increased Nf1+/- mast cell migration. Thus, these studies identify a novel interaction between Nf1-/- Schwann cells and Nf1+/- mast cells that is likely to be important in neurofibroma formation.
Yang
Feng-Chun
FC
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Ingram
David A
DA
Chen
Shi
S
Hingtgen
Cynthia M
CM
Ratner
Nancy
N
Monk
Kelly R
KR
Clegg
Travis
T
White
Hilary
H
Mead
Laura
L
Wenning
Mary Jo
MJ
Williams
David A
DA
Kapur
Reuben
R
Atkinson
Simon J
SJ
Clapp
D Wade
DW
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002465:Cell Movement; D003470:Culture Media / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016514:Genes, Neurofibromatosis 1; D006579:Heterozygote; D006720:Homozygote; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009455:Neurofibroma / Q000378:metabolism; D025542:Neurofibromin 1 / Q000235:genetics* / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D012583:Schwann Cells / Q000378:metabolism*; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism; D013997:Time Factors
D003470:Culture Media; D025542:Neurofibromin 1; D019089:Stem Cell Factor