title: The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells.
abstract: Neurofibromatosis is caused by the loss of neurofibromin (Nf1), leading to peripheral nervous system (PNS) tumors, including neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). A long-standing question has been whether these tumors arise from neural crest stem cells (NCSCs) or differentiated glia. Germline or conditional Nf1 deficiency caused a transient increase in NCSC frequency and self-renewal in most regions of the fetal PNS. However, Nf1-deficient NCSCs did not persist postnatally in regions of the PNS that developed tumors and could not form tumors upon transplantation into adult nerves. Adult P0a-Cre+Nf1(fl/-) mice developed neurofibromas, and Nf1(+/-)Ink4a/Arf(-/-) and Nf1/p53(+/-) mice developed MPNSTs, but NCSCs did not persist postnatally in affected locations in these mice. Tumors appeared to arise from differentiated glia, not NCSCs.
authors.affiliation: Center for Stem Cell Biology, Howard Hughes Medical Institute, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109-2216, USA.
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Joseph
authors.forename: Jack T
authors.initials: JT
authors.lastname: Mosher
authors.forename: Johanna
authors.initials: J
authors.lastname: Buchstaller
authors.forename: Paige
authors.initials: P
authors.lastname: Snider
authors.forename: Paul E
authors.initials: PE
authors.lastname: McKeever
authors.forename: Megan
authors.initials: M
authors.lastname: Lim
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Morrison
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology; D009369:Neoplasms / Q000473:pathology*; D018317:Nerve Sheath Neoplasms / Q000473:pathology; D009432:Neural Crest / Q000166:cytology* / Q000187:drug effects; D018318:Neurofibroma, Plexiform / Q000473:pathology; D025542:Neurofibromin 1 / Q000172:deficiency*; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects; D017933:Peripheral Nervous System / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D025542:Neurofibromin 1; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins