Plexiform and Dermal Neurofibromas and Pigmentation Are Caused by Nf1 Loss in Desert Hedgehog-Expressing Cells

Neurofibromatosis type 1 ( Nf1) mutation predisposes to benign peripheral nerve (glial) tumors called neurofibromas. The point(s) in development when Nf1 loss promotes neurofibroma formation are unknown. We show that inactivation of Nf1 in the glial lineage in vitro at embryonic day 12.5 + 1, but no...

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Bibliographic Details
Published in:Cancer cell 2008-02, Vol.13 (2), p.105-116
Main Authors: Wu, Jianqiang, Williams, Jon P., Rizvi, Tilat A., Kordich, Jennifer J., Witte, David, Meijer, Dies, Stemmer-Rachamimov, Anat O., Cancelas, Jose A., Ratner, Nancy
Format: Article
Language:English
Subjects:
Animals
Axons - metabolism
Axons - pathology
Cell Proliferation
CELLCYCLE
Embryo Loss
Embryo, Mammalian - cytology
Ganglia, Spinal - cytology
Hedgehog Proteins - metabolism
Integrases - metabolism
Mice
Models, Biological
Neurofibroma, Plexiform - pathology
Neurofibroma, Plexiform - ultrastructure
Neurofibromin 1 - metabolism
Neuroglia - cytology
Neuroglia - metabolism
Peripheral Nerves - metabolism
Peripheral Nerves - pathology
Peripheral Nervous System Neoplasms - pathology
Pigmentation
Receptor, Nerve Growth Factor - metabolism
Recombination, Genetic
Schwann Cells - pathology
Schwann Cells - ultrastructure
Sciatic Nerve - metabolism
Sciatic Nerve - pathology
Stem Cells - cytology
Stem Cells - metabolism
STEMCELL
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Summary:Neurofibromatosis type 1 ( Nf1) mutation predisposes to benign peripheral nerve (glial) tumors called neurofibromas. The point(s) in development when Nf1 loss promotes neurofibroma formation are unknown. We show that inactivation of Nf1 in the glial lineage in vitro at embryonic day 12.5 + 1, but not earlier (neural crest) or later (mature Schwann cell), results in colony-forming cells capable of multilineage differentiation. In vivo, inactivation of Nf1 using a DhhCre driver beginning at E12.5 elicits plexiform neurofibromas, dermal neurofibromas, and pigmentation. Tumor Schwann cells uniquely show biallelic Nf1 inactivation. Peripheral nerve and tumors contain transiently proliferating Schwann cells that lose axonal contact, providing insight into early neurofibroma formation. We suggest that timing of Nf1 mutation is critical for neurofibroma formation.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2007.12.027